Substituted pyridine and pyrazine compounds as PDE4 inhibitors

ABSTRACT

The invention provides a chemical entity of Formula (I) 
                         
wherein R 1 , R 2 , R 3 , R 4 , Y and Z have any of the values described herein, and compositions comprising such chemical entities; methods of making them; and their use in a wide range of methods, including metabolic and reaction kinetic studies, detection and imaging techniques, and radioactive treatments; and therapies, including inhibiting PDE4, enhancing neuronal plasticity, treating neurological disorders, providing neuroprotection, treating a cognitive impairment associated with a CNS disorder, enhancing the efficiency of cognitive and motor training, providing neurorecovery and neurorehabilitation, enhancing the efficiency of non-human animal training protocols, and treating peripheral disorders, including inflammatory and renal disorders.

INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS

Any and all priority claims identified in the Application Data Sheet, orany correction thereto, are hereby incorporated by reference under 37CFR 1.57. For example, this application claims the benefit under 35U.S.C. §119(e) to U.S. Provisional Application No. 61/786,288, filed onMar. 14, 2013, which is incorporated herein by reference in itsentirety.

BACKGROUND

1. Field

The present invention relates to certain substituted pyridine andpyrazine compounds and derivatives of such compounds; pharmaceuticalcompositions containing them methods of making them; and their use invarious methods, including the inhibition of PDE4 enzymes; detection andimaging techniques; enhancing neuronal plasticity; treating neurologicaldisorders, including psychiatric, neurodegenerative, cerebrovascular,and cognitive disorders; providing neuroprotection; enhancing theefficiency of cognitive and motor training; facilitating neurorecoveryand neurorehabilitation; and treating peripheral disorders, includinginflammatory and renal disorders.

2. Description of the Related Technology

The mammalian phosphodiesterases (PDEs) are a group of closely relatedenzymes divided into 11 families (PDE1-11) based on substratespecificity, inhibitor sensitivity and more recently, on sequencehomology. The 11 families are coded by 21 genes, providing several ofthe families with multiple members. All mammalian PDEs share a conservedcatalytic domain located in the COOH-terminal portion of the protein. InGAF-containing PDEs, one or both GAFs can provide dimerization contacts.In addition, one of the GAFs in each of these proteins provides forallosteric cGMP binding (PDE2, PDE5, PDE6, PDE11), allosteric cAMPbinding (PDE10), and regulation of catalytic site functions (PDE2, PDE5,PDE6). The other families of PDEs have unique complements of varioussubdomains (UCR, NHR, PAS, membrane association) that contribute toregulation of activity. PDEs 1, 2, 3, and 4 are expressed in manytissues, whereas others are more restricted. In most cells, PDE3 andPDE4 provide the major portion of cAMP-hydrolyzing activity (Francis,Physiological Reviews, 2011, 91, 651-690).

The PDE4 family includes four isoforms (PDE4A, B, C and D) with morethan 20 splice variants, making it one of the largest PDE subfamilies(Bender and Beavo, Pharmacol. Rev., 2006, 58 (3), 488-520). PDE4 enzymeshydrolyze cAMP with a substrate apparent Km of 1-5 uM for cAMP. The PDE4enzyme is reported to be regulated by two upstream conserved region(UCR) domains. Depending on differential RNA splicing, PDE4 variants canbe distinguished into two major subgroups: long and short forms (Contiet al., J Biol. Chem., 2003, 278, 5493-5496). Nine splice variants havebeen reported. PDE4D1, 4D2 and 4D6 all are shorter forms lacking UCRs.PDE4D3, 4D4, 4D5, 4D7, 4D8 and 4D9 are longer forms that contain bothUCRs and N terminal domains important for their subcellular localization(Bender and Beavo, 2006). Long form PDE4D3 activity is increased by PKAphosphorylation via Ser54 in the N-terminal UCR1 (Alvarez et al., Mol.Pharmacol., 1995, 48, 616-622; Sette et al., J Biol. Chem., 1996, 271,16526-16534). Conversely, Erk2 phosphorylation of Ser597 in theC-terminus of PDE4D3 causes a reduction in catalytic activity. One orseveral PDE4D isoforms are expressed throughout most tissues tested,including cortex, hippocampus, cerebellum, heart, liver, kidney, lungand testis (Richter et al., Biochem. J., 2005, 388, 803-811). Thelocalization and regulation of PDE4D isoforms is thought to allow fortight and local regulation of cAMP levels, possibly limiting signalpropagation in specific subcellular compartments.

Numerous studies have highlighted a role for PDEs generally, and PDE4 inparticular, in modulating intracellular signaling pathways that regulatemany physiological processes, including those underling neuralplasticity, cognition, and memory. In particular, PDEs play an importantrole in intracellular signal transduction pathways involving the secondmessengers. cAMP and cGMP. These cyclic nucleotides function asubiquitous intracellular signaling molecules in all mammalian cells. PDEenzymes hydrolyze cAMP and cGMP by breaking phosphodiester bonds to formthe corresponding monophosphates (Bender and Beavo, Pharmacol. Rev.,2006, 58 (3), 488-520). PDE activities are modulated in coordinationwith adenylyl cyclase (AC) and guanylyl cyclase (GC) activities throughdirect effectors and feedback pathways, thereby maintaining cAMP andcGMP levels within optimum ranges for responsiveness to signals. Theability of extracellular signals to modulate the intracellularconcentration of cyclic nucleotides allows cells to respond to externalstimuli across the boundary of the cell membrane.

The cyclic nucleotide signaling cascades have been adapted to respond toa host of transduction systems including G-protein coupled receptors(GPCRs) and voltage and ligand gated ion channels. Cyclic nucleotidestransmit their signal in the cell through a variant of tertiaryelements. The best described of these are cAMP dependent protein kinase(PKA) and cGMP dependent protein kinase (PKG). The binding of the cyclicnucleotide to each enzyme enables the phosphorylation of downstreamenzymes and proteins functioning as effectors or additional elements inthe signaling cascade. Of particular importance to memory formation iscAMP activation of PKA, which phosphorylates cAMP responseelement-binding protein (CREB). pCREB is an activated transcriptionfactor, which binds to specific DNA loci and initiates transcription ofmultiple genes involved in neuronal plasticity. Both in vitro and invivo studies have associated alterations in cyclic nucleotideconcentrations with biochemical and physiological process linked tocognitive function (Kelly and Brandon, Progress in Brain Research, 2009,179, 67-73; Schmidt, Current Topics in Medicinal Chemistry, 2010, 10,222-230). Signal intensity and the levels of coincident activity at asynapse are established variables that can result in potentiation oftransmission at a particular synapse. Long term potentiation (LTP) isthe best described of these processes and is known to be modulated byboth the cAMP and cGMP signaling cascades.

Focus on the role of PDE4 in memory stems from the discovery of thePDE4-like Drosophila learning mutant dunce (dnc gene), a cyclicnucleotide phosphodiesterase of the PDE4 subtype (Yun and Davis, NucleicAcids Research, 1989, 17(20), 8313-8326). The dnc mutant flies aredefective in acquisition and/or short-term memory when tested in severaldifferent olfactory associative learning situations, with negative(Dudai et al., Proc Natl Acad. Sci., 1976, 73(5), 1684-1688; Dudai Y.,Proc Natl Acad. Sci., 1983, 80(17), 5445-5448; Tully and Quinn, Journalof Comparative Physiology, 1985, 157(2), 263-77) or positivereinforcement (Tempel et al., Proc Natl Acad. Sci., 1983, 80(5),1482-1486). In mammals, PDE4D knockout animals display decreasedimmobility in the antidepressant tail-suspension and forced swim testmodels (Zhang et al., Neuropsychopharmacology, 2002, 27(4), 587-595),enhanced in vitro LTP in hippocampal CA1 slices (Rutten et al., Eur. J.Neurosci., 2008, 28(3), 625-632), and enhanced memory in radial maze,object recognition, and Morris water maze tasks (Li et al., J.Neurosci., 2011, 31, 172-183).

Such observations highlight the interest in PDE-inhibition, includingPDE4-inhibition, as a therapeutic target for numerous disorders and incognitive enhancement. For example, by increasing cAMP levels, suchinhibitors may be useful in treating cognitive deterioration inneurodegenerative disorders such Parkinson's Disease and Alzheimer'sDisease, as well as generally improving cognition in normal, diseased,and aging subjects. Various small-molecule PDE4 enzyme inhibitors havebeen reported e.g., Aza-bridged bicycles (DeCODE Genetics; Intl. Pat.Appl. Publ. WO 2010059836, May 27, 2010); N-substituted anilines (MemoryPharmaceuticals Corporation; Intl. Pat. Appl. Publ. WO 2010003084, Jan.7, 2010); Biaryls (DeCODE Genetics; Intl. Pat. Appl. Publ. WO2009067600, May 28, 2009, WO 2009067621, May 28, 2009); Benzothiazolesand benzoxazoles (DeCODE Genetics; U.S. Pat. Appl. Publ. US 20090130076,May 21, 2009); Catechols (DeCODE Genetics; U.S. Pat. Appl. Publ. US20090131530, May 21, 2009), Pteridines (Boehringer IngelheimInternational G.m.b.H.; U.S. Pat. No. 7,674,788, Nov. 29, 2007);Heteroaryl pyrazoles (Memory Pharmaceuticals Corporation; Intl. Pat.Appl. Publ. WO 2007123953, Nov. 1, 2007); Naphthyridines (Glaxo GroupLimited; Intl. Pat. Appl. Publ. WO 2006053784, May 26, 2006);Piperazinyldihydrothienopyrimidines (Boehringer Ingelheim InternationalG.m.b.H.; EP Pat. 1,874,781, Jun. 24, 2009); Nicotinamide derivatives(Pfizer; U.S. Pat. Appl. Publ. US 20050020587, Jan. 27, 2005);Heteroarylmethyl phenyl amines (Memory Pharmaceuticals Corporation; U.S.Pat. No. 7,087,625, Aug. 8, 2006); Naphthyridines (Novartis AG; EP Pat.1,443,925, Dec. 26, 2007; U.S. Pat. No. 7,468,370, Dec. 23, 2008).

However, PDE4 inhibitors have generally been associated with numerousside effects—most notably emesis—that have typically limited theirusefulness and tolerability (e.g., Giembycz, Curr. Opin. Pharm. 2005, 5,238-244). It is therefore desirable to develop improved PDE4 inhibitorsshowing higher potency, greater specificity, and better side effectprofiles. The present invention meets these and other needs in the artby disclosing substituted pyridine and pyrazine compounds as potent andwell-tolerated PDE4 inhibitors.

SUMMARY

The invention provides a chemical entity of Formula (I):

wherein R¹, R², R³, R⁴, Y and Z have any of the values described herein.

In one aspect the chemical entity is selected from the group consistingof compounds of Formula (I), pharmaceutically acceptable salts ofcompounds of Formula (I), pharmaceutically acceptable prodrugs ofcompounds of Formula (I), and pharmaceutically acceptable metabolites ofcompounds of Formula (I).

Chemical entities of compounds of Formula (I) are useful in wide rangeof methods. Isotopically-labeled compounds and prodrugs can be used inmetabolic and reaction kinetic studies, detection and imagingtechniques, and radioactive treatments. The chemical embodiments of thepresent invention can be used to inhibit PDE4, in particular; to treat adisorder mediated by PDE4, in particular; to enhance neuronalplasticity; to treat neurological disorders, including neurodegenerativedisorders, cognitive disorders, and cognitive deficits associated withCNS disorders; to confer neuroprotection; and to treat peripheraldisorders, including inflammatory and renal disorders. The chemicalembodiments of the present invention are also useful as augmentingagents to enhance the efficiency of cognitive and motor training, tofacilitate neurorecovery and neurorehabilitation, and to increase theefficiency of non-human animal training protocols. The invention isfurther directed to the general and specific embodiments defined,respectively, by the independent and dependent claims appended hereto,which are incorporated by reference herein.

DETAILED DESCRIPTION

The invention may be more fully appreciated by reference to thefollowing description, including the examples. Unless otherwise defined,all technical and scientific terms used herein have the same meaning ascommonly understood by one of ordinary skill in the art. Althoughmethods and materials similar or equivalent to those described hereincan be used in the practice or testing of the present invention,suitable methods and materials are described herein. In addition, thematerials, methods, and examples are illustrative only and not intendedto be limiting.

For the sake of brevity, all publications, including patentapplications, patents, and other citations mentioned herein, areincorporated by reference in their entirety. Citation of any suchpublication, however, shall not be construed as an admission that it isprior art to the present invention.

Abbreviations

The specification includes numerous abbreviations, whose meanings arelisted in the following Table:

Abbreviation Meaning ACN Acetonitrile AcOH Acetic Acid AIBN2,2′-Azobis(2-methylpropionitrile) BOC tert-Butyl dicarbonate n-BuLin-Butyl lithium DCM Dichloromethane Deoxo-Fluor ®Bis(2-methoxyethyl)aminosulfur trifluoride Dess-Martin1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benz- Reagent ® iodoxol-3(1H)-oneDIPEA, N,N-Ethyl-diisopropylamine or N,N-Diiso- Hünig's basepropyl-ethyl amine DMA N,N-Dimethylacetamide DMF N,N-DimethylformamideDMSO Dimethylsulfoxide dppf 1,1′-Bis(diphenylphosphino)ferrocene EtOAc,or EA Ethyl Acetate EtOH Ethanol HOAc or AcOH Acetic Acid HPLCHigh-performance liquid chromatography LAH Lithium aluminum hydrideLCMS, LC/MS Liquid chromatography-mass spectrometry MeOH Methanol NBSn-Bromosuccinimide, PdCI₂(dppf)- [1′1′-Bis(diphenylphosphino)ferro- DCMadduct cene]palladium(II) dichloride dichloromethane adduct Pd(PPh₃)₄Tetrakis[triphenylphosphine]palladium(0) TBAF Tetrabutylammoniumflouride TEA, Et₃N Triethylamine TFA Trifluoroacetic acid THFTetrahydrofuran TLC Thin layer chromatography XtalFluor ®(Diethylamino)difluorosulfonium tetrafluoroborate

TERMS AND DEFINITIONS

The use of subheadings such as “General,” “Chemistry,” “Compositions,”“Formulations,” etc., in this section, as well as in other sections ofthis application, are solely for convenience of reference and notintended to be limiting.

General

As used herein, the term “about” or “approximately” means within anacceptable range for a particular value as determined by one skilled inthe art, and may depend in part on how the value is measured ordetermined, e.g., the limitations of the measurement system ortechnique. For example, “about” can mean a range of up to 20%, up to10%, up to 5%, or up to 1% or less on either side of a given value.Alternatively, with respect to biological systems or processes, the term“about” can mean within an order of magnitude, within 5 fold, or within2 fold on either side of a value. Numerical quantities given herein areapproximate unless stated otherwise, meaning that the term “about” or“approximately” can be inferred when not expressly stated

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that, whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation of such given valuethat would reasonably be inferred based on the ordinary skill in theart, including equivalents and approximations due to the experimentaland/or measurement conditions for such given value. Whenever a yield isgiven as a percentage, such yield refers to a mass of the entity forwhich the yield is given with respect to the maximum amount of the sameentity for which that could be obtained under the particularstoichiometric conditions. Concentrations that are given as percentagesrefer to mass ratios, unless indicated differently.

As used herein, the terms “a,” “an,” and “the” are to be understood asmeaning both singular and plural, unless explicitly stated otherwise.Thus, “a,” “an,” and “the” (and grammatical variations thereof whereappropriate) refer to one or more.

A group of items linked with the conjunction “and” should not be read asrequiring that each and every one of those items be present in thegrouping, but rather should be read as “and/or” unless expressly statedotherwise. Similarly, a group of items linked with the conjunction “or”should not be read as requiring mutual exclusivity among that group, butrather should also be read as “and/or” unless expressly statedotherwise. Furthermore, although items, elements or components of theinvention may be described or claimed in the singular, the plural iscontemplated to be within the scope thereof unless limitation to thesingular is explicitly stated.

The terms “comprising” and “including” are used herein in their open,non-limiting sense. Other terms and phrases used in this document, andvariations thereof, unless otherwise expressly stated, should beconstrued as open ended as opposed to limiting. As examples of theforegoing: the term “example” is used to provide exemplary instances ofthe item in discussion, not an exhaustive or limiting list thereof;adjectives such as “conventional,” “traditional,” “normal,” “criterion,”“known,” and terms of similar meaning should not be construed aslimiting the item described to a given time period or to an itemavailable as of a given time, but instead should be read to encompassconventional, traditional, normal, or criterion technologies that may beavailable or known now or at any time in the future. Likewise, wherethis document refers to technologies that would be apparent or known toone of ordinary skill in the art, such technologies encompass thoseapparent or known to the skilled artisan now or at any time in thefuture.

The presence of broadening words and phrases such as “one or more,” “atleast,” “but not limited to” or other like phrases in some instancesshall not be read to mean that the narrower case is intended or requiredin instances where such broadening phrases may be absent. As will becomeapparent to one of ordinary skill in the art after reading thisdocument, the illustrated embodiments and their various alternatives maybe implemented without confinement to the illustrated examples.

Chemistry

The term “alkyl” refers to a fully saturated aliphatic hydrocarbongroup. The alkyl moiety may be a straight- or branched-chain alkyl grouphaving from 1 to 12 carbon atoms in the chain. Examples of alkyl groupsinclude, but are not limited to, methyl (Me, which also may bestructurally depicted by the symbol, “

”), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, andgroups that in light of the ordinary skill in the art and the teachingsprovided herein would be considered equivalent to any one of theforegoing examples.

The term “haloalkyl” refers to the alkyl moiety, which may be astraight- or branched-chain alkyl group having from 1 to 12 carbon atomsin the chain substituted with a halo group. Examples of haloalkyl groupsinclude, but are not limited to, —CF₃, —CHF₂, —CH₂F, —CH₂CF₃, —CH₂CHF₂,—CH₂CH₂F, —CH₂CH₂Cl, or —CH₂CF₂CF₃.

The term “cyano” refers to the group —CN.

The term “cycloalkyl” refers to a saturated or partially saturatedcarbocycle, such as monocyclic, fused polycyclic, bridged monocyclic,bridged polycyclic, spirocyclic, or spiro polycyclic carbocycle havingfrom 3 to 12 ring atoms per carbocycle. Where the term cycloalkyl isqualified by a specific characterization, such as monocyclic, fusedpolycyclic, bridged polycyclic, spirocyclic, and spiro polycyclic, thensuch term cycloalkyl refers only to the carbocycle so characterized.Illustrative examples of cycloalkyl groups include the followingentities, in the form of properly bonded moieties:

Those skilled in the art will recognize that the species of cycloalkylgroups listed or illustrated above are not exhaustive, and thatadditional species within the scope of these defined terms may also beselected.

The term “halogen” represents chlorine, fluorine, bromine or iodine. Theterm “halo” represents chloro, fluoro, bromo or iodo.

The term “heteroatom” used herein refers to, for example, O (oxygen), S(sulfur) and N (nitrogen).

The term “heteroaryl” refers to a monocyclic, fused bicyclic, or fusedpolycyclic aromatic heterocycle (ring structure having ring atomsselected from carbon atoms and up to four heteroatoms selected fromnitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms perheterocycle. Illustrative examples of heteroaryl groups include thefollowing entities, in the form of properly bonded moieties:

The term “substituted” means that the specified group or moiety bearsone or more substituents. The term “unsubstituted” means that thespecified group bears no substituents. The term “optionally substituted”means that the specified group is unsubstituted or substituted by one ormore substituents. Where the term “substituted” is used to describe astructural system, the substitution is meant to occur at anyvalency-allowed position on the system. In cases where a specifiedmoiety or group is not expressly noted as being optionally substitutedor substituted with any specified substituent, it is understood thatsuch a moiety or group is intended to be unsubstituted.

Formulas

Any formula given herein is intended to represent compounds havingstructures depicted by the structural formula as well as certainvariations or forms. In particular, compounds of any formula givenherein may have asymmetric centers and therefore exist in differentenantiomeric forms. All optical isomers and stereoisomers of thecompounds of the general formula, and mixtures thereof, are consideredwithin the scope of the formula. Thus, any formula given herein isintended to represent a racemate, one or more enantiomeric forms, one ormore diastereomeric forms, one or more atropisomeric forms, and mixturesthereof. Furthermore, certain structures may exist as geometric isomers(i.e., cis and trans isomers), as tautomers, or as atropisomers.

The symbols

and

are used as meaning the same spatial arrangement in chemical structuresshown herein. Analogously, the symbols

and

are used as meaning the same spatial arrangement in chemical structuresshown herein.

Compounds

As used herein, a “compound” refers to any one of: (a) the actuallyrecited form of such compound, and (b) any of the forms of such compoundin the medium in which the compound is being considered when named. Forexample, reference herein to a compound such as R—COOH, encompassesreference to any one of, for example, R—COOH(s), R—COOH(sol), andR—COO-(sol). In this example, R—COOH(s) refers to the solid compound, asit could be for example in a tablet or some other solid pharmaceuticalcomposition or preparation; R—COOH(sol) refers to the undissociated formof the compound in a solvent; and R—COO-(sol) refers to the dissociatedform of the compound in a solvent, such as the dissociated form of thecompound in an aqueous environment, whether such dissociated formderives from R—COOH, from a salt thereof, or from any other entity thatyields R—COO— upon dissociation in the medium being considered.

As used herein, the term “chemical entity” collectively refers to acompound, along with the derivatives of the compound, including salts,chelates, solvates, conformers, non-covalent complexes, metabolites, andprodrugs.

In one aspect the chemical entity is selected from the group consistingof compounds of Formula (I), pharmaceutically acceptable salts ofcompounds of Formula (I), pharmaceutically acceptable prodrugs ofcompounds of Formula (I), and pharmaceutically acceptable metabolites ofcompounds of Formula (I).

In another example, an expression such as “exposing an entity tocompound of formula R—COOH” refers to the exposure of such entity to theform, or forms, of the compound R—COOH that exists, or exist, in themedium in which such exposure takes place. In still another example, anexpression such as “reacting an entity with a compound of formulaR—COOH” refers to the reacting of (a) such entity in the chemicallyrelevant form, or forms, of such entity that exists, or exist, in themedium in which such reacting takes place, with (b) the chemicallyrelevant form, or forms, of the compound R—COOH that exists, or exist,in the medium in which such reacting takes place. In this regard, ifsuch entity is for example in an aqueous environment, it is understoodthat the compound R—COOH is in such same medium, and therefore theentity is being exposed to species such as R—COOH(aq) and/or R—COO-(aq),where the subscript “(aq)” stands for “aqueous” according to itsconventional meaning in chemistry and biochemistry. A carboxylic acidfunctional group has been chosen in these nomenclature examples; thischoice is not intended, however, as a limitation but it is merely anillustration. It is understood that analogous examples can be providedin terms of other functional groups, including but not limited tohydroxyl, basic nitrogen members, such as those in amines, and any othergroup that interacts or transforms according to known manners in themedium that contains the compound. Such interactions and transformationsinclude, but are not limited to, dissociation, association, tautomerism,solvolysis, including hydrolysis, solvation, including hydration,protonation and deprotonation. No further examples in this regard areprovided herein because these interactions and transformations in agiven medium are known by any one of ordinary skill in the art.

In another example, a zwitterionic compound is encompassed herein byreferring to a compound that is known to form a zwitterion, even if itis not explicitly named in its zwitterionic form. Terms such aszwitterion, zwitterions, and their synonyms zwitterionic compound(s) arestandard IUPAC-endorsed names that are well known and part of standardsets of defined scientific names. In this regard, the name zwitterion isassigned the name identification CHEBI:27369 by the Chemical Entities ofBiological Interest (ChEBI) dictionary of molecular entities. As isgenerally well known, a zwitterion or zwitterionic compound is a neutralcompound that has formal unit charges of opposite sign. Sometimes thesecompounds are referred to by the term “inner salts”. Other sources referto these compounds as “dipolar ions”, although the latter term isregarded by still other sources as a misnomer. As a specific example,aminoethanoic acid (the amino acid glycine) has the formula H₂NCH₂COOH,and it exists in some media (in this case in neutral media) in the formof the zwitterion +H₃NCH₂COO—. Zwitterions, zwitterionic compounds,inner salts, and dipolar ions in the known and well established meaningsof these terms are within the scope of this invention, as would in anycase be so appreciated by those of ordinary skill in the art. Becausethere is no need to name each and every embodiment that would berecognized by those of ordinary skill in the art, no structures of thezwitterionic compounds that are associated with the compounds of thisinvention are given explicitly herein. They are, however, part of theembodiments of this invention. No further examples in this regard areprovided herein because the interactions and transformations in a givenmedium that lead to the various forms of a given compound are known byany one of ordinary skill in the art.

Isotopes may be present in the compounds described. Each chemicalelement present in a compound either specifically or genericallydescribed herein may include any isotope of said element. Any formulagiven herein is also intended to represent unlabeled forms as well asisotopically labeled forms of the compounds. Isotopically labeledcompounds have structures depicted by the formulas given herein exceptthat one or more atoms are replaced by an atom having a selected atomicmass or mass number. Examples of isotopes that can be incorporated intocompounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as ²H, ³H,¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²⁵I,respectively.

When referring to any formula given herein, the selection of aparticular moiety from a list of possible species for a specifiedvariable is not intended to define the same choice of the species forthe variable appearing elsewhere. In other words, where a variableappears more than once, the choice of the species from a specified listis independent of the choice of species for the same variable elsewherein the formula, unless otherwise stated.

By way of a first example on substituent terminology, if substituent S¹_(example) is one of S₁ and S₂, and substituent S² _(example) is one ofS₃ and S₄, then these assignments refer to embodiments of this inventiongiven according to the choices S¹ _(example) is S₁ and S² _(example) isS₃; S¹ _(example) is S₁ and S² _(example) is S₄; S¹ _(example) is S₂ andS² _(example) is S₃; S¹ _(example) is S₂ and S² _(example) is S₄; andequivalents of each one of such choices. The shorter terminology “S¹_(example) is one of S₁ and S₂ and “S² _(example) is one of S₃ and S₄ isaccordingly used herein for the sake of brevity but not by way oflimitation. The foregoing first example on substituent terminology,which is stated in generic terms, is meant to illustrate the varioussubstituent assignments described herein. The foregoing convention givenherein for substituents extends, when applicable, to members such as R¹,R², R³, R⁴ R^(a), R^(b), R^(c), R^(d), R^(d1), R^(e), R^(e1), R^(f),R^(g), R^(h), R^(j), R^(k) R^(m), R^(n) and U, Y, Z, HAL, and any othergeneric substituent symbol used herein.

Furthermore, when more than one assignment is given for any member orsubstituent, embodiments of this invention comprise the variousgroupings that can be made from the listed assignments, takenindependently, and equivalents thereof. By way of a second example onsubstituent terminology, if it is herein described that substituentS_(example) is one of S₁, S₂ and S₃, the listing refers to embodimentsof this invention for which S_(example) is S₁; S_(example) is S₂;S_(example) is S³; S_(example) is one of S₁ and S₂; S_(example) is oneof S₁ and S₃; S_(example) is one of S₂ and S₃; S_(example) is one of S₁,S₂ and S₃; and S_(example) is any equivalent of each one of thesechoices. The shorter terminology “S_(example) is one of S₁, S₂ and S₃”is accordingly used herein for the sake of brevity, but not by way oflimitation. The foregoing second example on substituent terminology,which is stated in generic terms, is meant to illustrate the varioussubstituent assignments described herein. The foregoing convention givenherein for substituents extends, when applicable, to members such as R¹,R², R³, R⁴ R^(a), R^(b), R^(c), R^(d), R^(d1), R^(e), Rf, R^(g), R^(h),R^(j), R^(k) R^(m), R^(n) and U, Y, Z, HAL, and any other genericsubstituent symbol used herein.

The nomenclature “C_(i-j)” with j>i, when applied herein to a class ofsubstituents, is meant to refer to embodiments of this invention forwhich each and every one of the number of carbon members, from i to jincluding i and j, is independently realized. By way of example, theterm C₁₋₃ refers independently to embodiments that have one carbonmember (C₁), embodiments that have two carbon members (C₂), andembodiments that have three carbon members (C₃).

The term C_(n-m)alkyl refers to an aliphatic chain, whether straight orbranched, with the total number N of carbon members in the chain thatsatisfies n≦N≦m, with m>n.

Any disubstituent referred to herein is meant to encompass the variousattachment possibilities when more than one of such possibilities areallowed. For example, reference to disubstituent -A-B-, where A≠B,refers herein to such disubstituent with A attached to a firstsubstituted member and B attached to a second substituted member, and italso refers to such disubstituent with A attached to the second memberand B attached to the first substituted member.

According to the foregoing interpretive considerations on assignmentsand nomenclature, it is understood that explicit reference herein to aset implies, where chemically meaningful and unless indicated otherwise,independent reference to embodiments of such set, and reference to eachand every one of the possible embodiments of subsets of the set referredto explicitly.

The term “prodrug” means a precursor of a designated compound that,following administration to a subject, yields the compound in vivo via achemical or physiological process such as solvolysis or enzymaticcleavage, or under physiological conditions (e.g., a prodrug on beingbrought to physiological pH is converted to the compound of Formula(I)).

A “pharmaceutically acceptable prodrug” is a prodrug that is non-toxic,biologically tolerable, and otherwise biologically suitable foradministration to the subject. Illustrative procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

A “metabolite” means a pharmacologically active product of metabolism inthe body of a compound of Formula (I) or salt thereof. Preferably, themetabolite is in an isolated form outside the body.

Compositions

The term “composition,” as in pharmaceutical composition, is intended toencompass a product comprising the active ingredient(s), and the inertingredient(s) (pharmaceutically acceptable excipients) that make up thecarrier, as well as any product which results, directly or indirectly,from combination, complexation, or aggregation of any two or more of theingredients, or from dissociation of one or more of the ingredients, orfrom other types of reactions or interactions of one or more of theingredients. Accordingly, the pharmaceutical compositions of the presentinvention encompass any composition made by admixing a compound ofFormula (I) and a pharmaceutically acceptable excipient.

The term “pharmaceutically acceptable,” as used in connection withcompositions of the invention, refers to molecular entities and otheringredients of such compositions that are physiologically tolerable anddo not typically produce untoward reactions when administered to ananimal (e.g., human). The term “pharmaceutically acceptable” may alsomean approved by a regulatory agency of the Federal or a stategovernment or listed in the U.S. Pharmacopeia or other generallyrecognized pharmacopeia for use in animals (e.g. mammals), and moreparticularly in humans.

A “pharmaceutically acceptable excipient” refers to a substance that isnon-toxic, biologically tolerable, and otherwise biologically suitablefor administration to a subject, such as an inert substance, added to apharmacological composition or otherwise used as a vehicle, carrier, ordiluents to facilitate administration of an agent and that is compatibletherewith. Examples of excipients include calcium carbonate, calciumphosphate, various sugars and types of starch, cellulose derivatives,gelatin, vegetable oils, and polyethylene glycols. Suitablepharmaceutical carriers include those described in Remington: TheScience and Practice of Pharmacy, 21st Ed., Lippincott Williams &Wilkins (2005).

A “pharmaceutically acceptable salt” is intended to mean a salt of afree acid or base of a compound represented by Formula (I) that isnon-toxic, biologically tolerable, or otherwise biologically suitablefor administration to the subject. See, generally, G. S. Paulekuhn etal., Trends in Active Pharmaceutical Ingredient Salt Selection based onAnalysis of the Orange Book Database, J. Med. Chem. 2007, 50, 6665-6672;Berge et al., Pharmaceutical Salts, J. Pharm. Sci. 1977, 66, 1-19; Stahland Wermuth (eds), Pharmaceutical Salts; Properties, Selection, and Use:2nd Revised Edition, Wiley-VCS, Zurich, Switzerland (2011). Examples ofpharmaceutically acceptable salts are those that are pharmacologicallyeffective and suitable for contact with the tissues of patients withoutundue toxicity, irritation, or allergic response. A compound of Formula(I) may possess a sufficiently acidic group, a sufficiently basic group,or both types of functional groups, and accordingly react with a numberof inorganic or organic bases, and inorganic and organic acids, to forma pharmaceutically acceptable salt bases, and inorganic and organicacids, to form a pharmaceutically acceptable salt.

The term “carrier” refers to an adjuvant, vehicle, or excipients, withwhich the compound is administered. In preferred embodiments of thisinvention, the carrier is a solid carrier. Suitable pharmaceuticalcarriers include those described in Remington: The Science and Practiceof Pharmacy, 21st Ed., Lippincott Williams & Wilkins (2005).

The term “dosage form,” as used herein, is the form in which the dose isto be administered to the subject or patient. The drug is generallyadministered as part of a formulation that includes nonmedical agents.The dosage form has unique physical and pharmaceutical characteristics.Dosage forms, for example, may be solid, liquid or gaseous. “Dosageforms” may include for example, a capsule, tablet, caplet, gel caplet(gelcap), syrup, a liquid composition, a powder, a concentrated powder,a concentrated powder admixed with a liquid, a chewable form, aswallowable form, a dissolvable form, an effervescent, a granulatedform, and an oral liquid solution. In a specific embodiment, the dosageform is a solid dosage form, and more specifically, comprises a tabletor capsule.

As used herein, the term “inert” refer to any inactive ingredient of adescribed composition. The definition of “inactive ingredient” as usedherein follows that of the U.S. Food and Drug Administration, as definedin 21 C.F.R. 201.3(b)(8), which is any component of a drug product otherthan the active ingredient.

Methods and Uses

As used herein, the term “disorder” is used interchangeably with“disease” or “condition”. For example, a CNS disorder also means a CNSdisease or a CNS condition.

As used herein, the term “cognitive impairment” is used interchangeablywith “cognitive dysfunction” or “cognitive deficit,” all of which aredeemed to cover the same therapeutic indications.

The terms “treating,” “treatment,” and “treat” cover therapeutic methodsdirected to a disease-state in a subject and include: (i) preventing thedisease-state from occurring, in particular, when the subject ispredisposed to the disease-state but has not yet been diagnosed ashaving it; (ii) inhibiting the disease-state, e.g., arresting itsdevelopment (progression) or delaying its onset; and (iii) relieving thedisease-state, e.g., causing regression of the disease state until adesired endpoint is reached. Treating also includes ameliorating asymptom of a disease (e.g., reducing the pain, discomfort, or deficit),wherein such amelioration may be directly affecting the disease (e.g.,affecting the disease's cause, transmission, or expression) or notdirectly affecting the disease.

As used in the present disclosure, the term “effective amount” isinterchangeable with “therapeutically effective amount” and means anamount or dose of a compound or composition effective in treating theparticular disease, condition, or disorder disclosed herein, and thus“treating” includes producing a desired preventative, inhibitory,relieving, or ameliorative effect. In methods of treatment according tothe invention, “an effective amount” of at least one compound accordingto the invention is administered to a subject (e.g., a mammal). An“effective amount” also means an amount or dose of a compound orcomposition effective to modulate activity of PDE4 or an associatedsignaling pathway, such as the CREB pathway and thus produce the desiredmodulatory effect. The “effective amount” will vary, depending on thecompound, the disease, the type of treatment desired, and its severity,and age, weight, etc.

The term “animal” is interchangeable with “subject” and may be avertebrate, in particular, a mammal, and more particularly, a human, andincludes a laboratory animal in the context of a clinical trial orscreening or activity experiment. Thus, as can be readily understood byone of ordinary skill in the art, the compositions and methods of thepresent invention are particularly suited to administration to anyvertebrate, particularly a mammal, and more particularly, a human.

As used herein, a “control animal” or a “normal animal” is an animalthat is of the same species as, and otherwise comparable to (e.g.,similar age, sex), the animal that is trained under conditionssufficient to induce transcription-dependent memory formation in thatanimal.

By “enhance,” “enhancing,” or “enhancement” is meant the ability topotentiate, increase, improve or make greater or better, relative tonormal, a biochemical or physiological action or effect. For example,enhancing long term memory formation refers to the ability to potentiateor increase long term memory formation in an animal relative to thenormal long term memory formation of the animal or controls. As aresult, long term memory acquisition is faster or better retained.Enhancing performance of a cognitive task refers to the ability topotentiate or improve performance of a specified cognitive task by ananimal relative to the normal performance of the cognitive task by theanimal or controls.

As used herein, the term “training protocol,” or “training,” refers toeither “cognitive training” or “motor training.” The phrase “inconjunction” means that a compound or composition of the presentinvention enhances CREB pathway function during cognitive or motortraining.

Reference will now be made to the embodiments of the present invention,examples of which are illustrated by and described in conjunction withthe accompanying drawings and examples. While certain embodiments aredescribed herein, it is understood that the described embodiments arenot intended to limit the scope of the invention. On the contrary, thepresent disclosure is intended to cover alternatives, modifications, andequivalents that can be included within the invention as defined by theappended claims.

Compounds

The present invention provides certain substituted pyridine and pyrazinederivatives, which are useful, for example, as inhibitors of PDE4enzymatic activity. They are distinct from tri-substituted pyridines aredisclosed in the following publications: U.S. Pat. No.7,399,761(Novartis AG, Nov. 14, 2002, CAS No. 1106203-18-2,1106203-16-0); Intl. Pat. Appl. Publ. WO 2003050098, (MaxiaPharmaceuticals, Jun. 19, 2003, CAS No. 544475-13-0, 544475-12-9) and JPPat. 4,321,737 (Intl. Pat. Appl. Publ. WO 9931062, Shionogi & Co., Jun.24, 1999, CAS No. 228096-03-5, 228096-04-6).

In its many embodiments, the invention is directed to a chemical entityof Formula (I):

wherein:Z is CH or N;

i) wherein when Z is CH, then;

R¹ is a member selected from the group consisting of: —H, —C₁₋₃alkyl and—C₁₋₃haloalkyl;

Y is —C(R^(a))₂—, where each R^(a) is independently selected from thegroup consisting of: —H, —F, —CH₃, —OH and —N(R^(b))₂;

R² is a member selected from the group consisting of:

-   -   A) phenyl unsubstituted or substituted with one or two R^(e)        members, where each R^(c) is independently selected from the        group consisting of: halo, —CN, —CO₂R^(b), —CONH₂, —SO₂CH₃,        —C(R^(b))₂OH, —CH₂NH₂, —CH₂CONH₂, —CH₂CO₂CH₃, —NHCONH₂,        —NHCONH-oxetane, —CONH-oxetane,

-   -   B) six-membered monocyclic heteroaromatic ring containing one or        two nitrogen members unsubstituted or substituted with one or        two members each independently selected from the group        consisting of: halo, —C₁₋₃alkyl, —C₁₋₃haloalkyl, —CN,        —C(R^(b))₂OH, —CH₂NH₂, —OC₁₋₃alkyl, —O—CH₂-cyclopropyl, —CO₂H,        —CON(R^(b))₂, —N(R^(b))₂, —NHCH₂CF₃, —NHCH(CH₃)₂,        —NHCH₂CH₂N(CH₃)₂, —NHcyclopropyl, and —NHCOCH₃;    -   C) five-membered monocyclic heteroaromatic ring containing two        to four nitrogen members unsubstituted or substituted with one        or two members each independently selected from the group        consisting of halo, —C₁₋₃alkyl, —C₁₋₃haloalkyl, —C(R^(b))₂OH,        —N(R^(b))₂, —NO₂, —CN, —OC₁₋₃alkyl, —CH₂OCH₃, —CH₂NH₂,        —CO₂C₁₋₃alkyl, —CO₂H, —CONH₂, —NHCOCH₃, and cyclopropyl; and    -   D) five or six-membered heteroaromatic ring selected from:        1,2-dihydro-pyridin-2-one, tetrazole, thiazole or oxazole each        unsubstituted or substituted with one or two members each        independently selected from the group consisting of —H, —CH₃,        and —NH₂;        R³ is a member selected from the group consisting of: phenyl,        pyridyl, thiophene, and pyrazole, each substituted with a member        selected from the group consisting of: halo, —C₁₋₃alkyl,        —C₁₋₃haloalkyl, —OC₁₋₃alkyl, —Ocyclopropyl, —OC₁₋₃haloalkyl,        —CN, —CH₂OH and —SO₂CH₃;        R⁴ is a member selected from the group consisting of —C₁₋₃alkyl        and —C₁₋₃haloalkyl; where each R^(b) is independently selected        from —H or —CH₃; and

ii) wherein when Z is N, then;

R¹ is —H;

Y is —CH₂—;

R² is a member selected from the group consisting of:

-   -   A) phenyl substituted with one or two R^(d) members, where each        R^(d) is independently selected from the group consisting of:        —CN, —CONH₂, and —CO₂C₁₋₃alkyl;    -   B) six-membered monocyclic heteroaromatic ring containing one or        two nitrogen members unsubstituted or substituted with a member        selected from the group consisting of: —CN, —OC₁₋₃alkyl, —CONH₂,        —N(R^(b))₂, and —NH-cyclopropyl;    -   C) five-membered monocyclic heteroaromatic ring containing two        or three nitrogen members unsubstituted or substituted with one        or two members each independently selected from the group        consisting of —C₁₋₃alkyl, —C₁₋₃haloalkyl, —CH₂OR^(b),        —N(R^(b))₂, —NO₂, —CO₂CH₃, and cyclopropyl; and    -   D) oxazole optionally substituted with one or two R^(b) members;        R³ is phenyl substituted with —Cl, —OC₁₋₃alkyl, or        —OC₁₋₃haloalkyl;        R⁴ is —C₁₋₃ alkyl; and        where each R^(b) is independently selected from —H or —CH₃.

In certain embodiments of compounds of Formula (I), Z is CH.

In certain embodiments of compounds of Formula (I), Z is N.

Some embodiments are given by compounds of Formula (I) where Z is CH,and R¹—H, —CH₃, or —CF₃.

In some of these embodiments, R¹ is —H.

In certain embodiments of compounds of Formula (I), Y is —CH₂—, —CH(F)—,—CH(OH)—, —C(OH)(CH₃)—, or —CH(CH₃)—, and Z is CH.

In some of these embodiments, Y is —CH₂—.

In certain embodiments of compounds of Formula (I), R² is

and R^(c) is —F, —CN, —CO₂H, —CONH₂, —SO₂CH₃, —C(CH₃)₂OH, —CH₂NH₂,—CH₂CONH₂, —CH₂CO₂CH₃, —NHCONH₂, —NHCONH-oxetane, —CONH-oxetane,

In some of these embodiments, R² is

and R^(c) is —F, —CONH₂, —CH₂CONH₂, —CH₂NH₂, —C(CH₃)₂OH, —SO₂CH₃, or—NHCONH₂.

In certain embodiments of compounds of Formula (I), Z is N and R² is4-cyanophenyl, 4-phenylamide or 4-phenylcarboxylic acid methyl ester.

Some embodiments are given by compounds of Formula (I) where R² ispyridine, unsubstituted or substituted with one or two members eachindependently selected from: —F, —C₁₋₃alkyl, —C₁₋₃haloalkyl,—OC₁₋₃alkyl, —OCH₂cyclopropyl, —CN, —N(R^(b))₂, —CH₂NH₂, —CO₂H,—CON(R^(b))₂, or —C(CH₃)₂OH.

In some of these embodiments, R² is

and R^(d) is —CH₃, —CF₃, —CN, —N(R^(b))₂, —CO₂H, —CON(R^(b))₂,—OC₁₋₃alkyl, —CH₂NH₂, —C(CH₃)₂OH, —OCH₂cyclopropyl, or —OCH(CH₃)₂.

In some of these embodiments, R² is

and R^(d) is —CH₃, —CF₃, —NH₂, —NHCH₃, —N(CH₃)₂, —CONH₂, —CONHCH₃,—CON(CH₃)₂, —OC₁₋₃alkyl, —C(CH₃)₂OH, or —OCH₂cyclopropyl.

In some of these embodiments, Z is N, and R² is

R^(d1) is —CN or —CONH₂.

Some embodiments are given by compounds of Formula (I) where R² ispyrazine, 6-methylpyridazin-3-amine or pyrimidine, where pyrimidine isunsubstituted or substituted with —Cl, —CH₃, —CN, —OC₁₋₃alkyl, —CO₂H,—CON(R^(b))₂, —C(CH₃)₂OH, —N(R^(b))₂, —NHCH₂CF₃, —NHCH(CH₃)₂,—CH₂CH₂N(CH₃)₂, —NHcyclopropyl, and —NHCOCH₃.

In some of these embodiments, R² is

and each R^(e) is independently —CH₃, —CN, —OCH₃, —CO₂H, —CONH₂,—C(CH₃)₂OH, —N(R^(b))₂, —NHCH₂CF₃, —NHCH(CH₃)₂, —CH₂CH₂N(CH₃)₂,—NHcyclopropyl, or —NHCOCH₃.

In some of these embodiments, R² is

and R^(e) is —CH₃, —CN, —OCH₃, —NH₂, —NHCH₃, —N(CH₃)₂, —NHCH₂CF₃,—NHcyclopropyl, —C(CH₃)₂OH, —CONH₂, —CONHCH₃, or —CON(CH₃)₂.

In some of these embodiments, Z is N, and R² is

unsubstituted or substituted with R^(e1), where R^(e1) is —CN, —OCH₃,—CONH₂, —NH₂, —NHCH₃, or —NHcyclopropyl.

Some embodiments are given by compounds of Formula (I) where R² isimidazole, pyrazole, and triazole, unsubstituted or substituted with oneor two members each independently selected from the group consisting of:—Cl, —CH₃, —CF₃, —CH₂OH, —NH₂, —NO₂, —CN, —CO₂C₁₋₃alkyl, —CO₂H, —CONH₂,or —NHCOCH₃.

In some of these embodiments, R² is

and R^(f) is —H, —Cl, —CH₃, —NO₂, —NH₂, —NHCOCH₃, —CH₂OH, —CN, —CONH₂,—CO₂H, or —CO₂CH₂CH₃.

In some of these embodiments, R² is

and R^(f) is —H, —NH₂, or —CH₂OH.

In some of these embodiments, R² is

where R^(g) is —H, —CH₃, —CH₂OH, or —NH₂.

Some embodiments are given by compounds of Formula (I) where R² is1H-tetrazole, 2H-tetrazole, 1,2-oxazole, 1,3-thiazole, eachindependently unsubstituted or substituted with —CH₃, or —NH₂.

Some embodiments are given by compounds of Formula (I) where R² is1,2,3-triazole and 1,2,4-triazole, each unsubstituted or substitutedwith —CH₃, —CH₂F, —CHF₂, —CF₃, —OCH₃, —OCH₂CH₃, —CN, —C(R^(b))OH,—CH₂OCH₃, N(R^(b))₂, —NO₂, —CO₂CH₃, —CONH₂, cyclopropyl or —CH₂NH₂.

In some of these embodiments, R² is

and R^(h) is —H, —CH₃, —CF₃, —CH₂F, —CHF₂, —OCH₃, —OCH₂CH₃, —CH₂OH,—C(CH₃)₂OH, —CH₂OCH₃, —NO₂, —NH₂, —NHCH₃, —N(CH₃)₂, —CN, —CONH₂,—CO₂CH₃, or -cyclopropyl.

In some of these embodiments, R² is

and R^(j) is —H, —CH₃, —CF₃, —OCH₃, —CH₂(OH), —C(CH₃)₂OH, —CH₂OCH₃,—CO₂CH₃, or —NO₂.

In some of these embodiments, R² is

and R^(k) is —H, —CH₃, —CF₃, —CH₂F, —CHF₂, —OCH₃, —OCH₂CH₃, —CH₂OH,—C(CH₃)₂OH, —CH₂OCH₃, —NO₂, —NH₂, —NHCH₃, —N(CH₃)₂, —CN, —CONH₂,—CO₂CH₃, or -cyclopropyl.

Some embodiments are given by compounds of Formula (I) where R³ is

and R^(m) is —Cl, —F, —CH₃, —CHF₂, —CN, —OCH₃, —CH₂OH, —OCH₂CH₃, —OCF₃,—OCHF₂, —SO₂CH₃, —OCH(CH₃)₂,

In some of these embodiments, R³ is 3-chlorophenyl, 3-cyanophenyl,3-fluorophenyl, 3-methylphenyl, 3-methoxyphenyl, 3-ethoxyphenyl,3-(trifluoromethoxy)phenyl, 3-(difluoromethoxy)phenyl or3-(difluoromethyl)phenyl.

Some embodiments are given by compounds of Formula (I) where R³ is

and R^(n) is H, —Cl, —CH₃, —OCH₃, —OCH₂CH₃, —OCHF₂, or —OCF₃.

In some of these embodiments, R³ is 4-chlorothiophen-2-yl,4-chloro-1H-pyrazol-1-yl, 1-methyl-1H-pyrazol-4-yl, and 1H-pyrazol-4-yl.

Some embodiments are given by compounds of Formula (I) where R⁴ is —CH₃,—CH₂CH₃, —CH(CH₃)₂, or —CHF₂.

Further embodiments are provided by pharmaceutically acceptable salts ofcompounds of Formula (I), pharmaceutically acceptable prodrugs ofcompounds of Formula (I), and pharmaceutically active metabolites ofcompounds of Formula (I).

In certain embodiments, a compound, or pharmaceutically acceptable saltthereof, of Formula (I) is selected from the group consisting of:

Ex Chemical Name 15-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyrimidine-2-carbonitrile 22-Chloro-5-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine3 {2-[(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)amino]ethyl}dimethylamine 42-Methoxy-3-(6-methoxypyridin-2-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine5 2-Methoxy-3-(3-methylphenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine 62-Methoxy-3-(5-methylpyridin-3-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine72-Methoxy-3-(2-methylpyridin-4-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine8{3-[2-Methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridin-3-yl]phenyl}methanol93-(3-Methanesulfonylphenyl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine102-Methoxy-3-(4-methylpyridin-2-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine112-Methoxy-3-(6-methylpyridin-2-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine122-(Difluoromethoxy)-3-(3-methylphenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine135-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyrimidine-2-carboxamide 14[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methanol 151-[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]-1-(4-fluorophenyl)ethan-1-ol16[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl](5-fluoropyridin-2-yl)methanol17 {[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methyl}(methyl)amine 18[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methanamine 19{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methyl}dimethylamine 203-(3-Chlorophenyl)-5-[fluoro(4-fluorophenyl)methyl]-2-methoxypyridine 214-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}benzoic acid 225-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}pyrimidine-2-carbonitrile235-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxylicacid 245-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxamide25 5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine26 (4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)urea 274-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}benzamide 283-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1H-pyrazol-4-ylmethyl)pyridine295-{[6-(Difluoromethoxy)-5-(3-methoxyphenyl)pyridin-3-yl]methyl}pyrimidin-2-amine 305-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridin-2-amine 311-(4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)-3-(oxetan-3-yl)urea 323-(3-Chlorophenyl)-2-methoxy-5-[(6-methoxypyridin-3-yl)methyl]pyridine335-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridin-2-amine345-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N,N-dimethylpyridin-2-amine 355-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyrimidine-2-carbonitrile 365-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1,3-thiazol-2-amine 37(2-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)methanol 385-{[5-(3-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine 395-{[5-(3-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carbonitrile40 5-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}pyrimidin-2-amine415-{[5-(3-Chlorophenyl)-6-(propan-2-yloxy)pyridin-3-yl]methyl}pyrimidin-2-amine 42 5-{[6-(Difluoromethoxy)-5-[3-(propan-2-yloxy)phenyl]pyridin-3-yl]methyl}pyrimidin-2-amine 435-{[6-(Difluoromethoxy)-5-[3-(oxetan-3-yloxy)phenyl]pyridin-3-yl]methyl}pyrimidin-2-amine 44N-(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)acetamide 45 3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(4-methanesulfonylphenyl)methyl]pyridine 465-{[6-(Difluoromethoxy)-5-(2-methoxypyridin-4-yl)pyridin-3-yl]methyl}pyrimidin-2-amine 475-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)pyrimidin-2-amine 482-[5-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)pyrimidin-2-yl]propan-2-ol 493-(3-Chlorophenyl)-2-methoxy-5-{[6-(trifluoromethyl)pyridin-3-yl]methyl}pyridine 503-(3-Chlorophenyl)-2-(difluoromethoxy)-5-{[6-(propan-2-yloxy)pyridin-3-yl]methyl}pyridine 513-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(6-propoxypyridin-3-yl)methyl]pyridine 525-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1-methyl-1,2-dihydropyridin-2-one 533-(3-Chlorophenyl)-2-methoxy-5-(pyridin-4-ylmethyl)pyridine 545-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridine-2-carboxylic acid 553-(3-Chlorophenyl)-2-methoxy-5-[(2-methoxypyrimidin-5-yl)methyl]pyrazine565-{[6-(3-chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-N-methylpyrimidin-2-amine 575-{[6-(3-chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-N-cyclopropylpyrimidin-2-amine 583-(3-Chlorophenyl)-2-methoxy-5-[(1-methyl-1H-pyrazol-4-yl)methyl]pyrazine59(4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)methanamine60 4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridin-2-amine613-(3-Chlorophenyl)-5-[(2,6-dimethylpyridin-4-yl)methyl]-2-methoxypyridine624-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridine-2-carbonitrile634-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridine-2-carboxamide64 3-(3-Chlorophenyl)-2-methoxy-5-(pyridin-3-ylmethyl)pyridine 653-(3-Chlorophenyl)-2-methoxy-5-(1,3-thiazol-5-ylmethyl)pyridine 663-(3-Chlorophenyl)-5-[(dimethyl-1,3-thiazol-5-yl)methyl]-2-methoxypyridine67 3-(3-Chlorophenyl)-2-methoxy-5-[(6-methoxy-5-methylpyridin-3-yl)methyl]pyridine 683-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1,3-thiazol-5-ylmethyl)pyridine69 3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(dimethyl-1,3-thiazol-5-yl)methyl]pyridine 705-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridine-3-carboxamide 71(5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridin-3-yl)methanamine 723-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(6-methylpyridin-3-yl)methyl]pyridine 733-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(2-methyl-1,3-thiazol-5-yl)methyl]pyridine 743-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1,3-thiazol-2-ylmethyl)pyridine755-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-2-methylpyrimidine765-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-2-methoxypyrimidine77 5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N-(propan-2-yl)pyrimidin-2-amine 785-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine 793-(3-Chlorophenyl)-2-methoxy-5-[(1-methyl-1H-pyrazol-4-yl)methyl]pyridine80 3-(3-Chlorophenyl)-2-methoxy-5-(1H-pyrazol-4-ylmethyl)pyridine 815-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N-methylpyrimidin-2-amine 825-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N-cyclopropylpyrimidin-2-amine 835-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N,N-dimethylpyrimidin-2-amine 845-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N-(2,2,2-trifluoroethyl)pyrimidin-2-amine 85 Methyl4-{[6-(3-chlorophenyl)-5-methoxypyrazin-2-yl]methyl}benzoate 864-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}benzonitrile 875-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}pyrimidin-2-amine 883-(3-Chlorophenyl)-5-[(4-fluorophenyl)methyl]-2-methoxypyridine 895-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyrimidin-2-amine 905-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}pyridine-2-carboxamide91 5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-N-cyclopropylpyrimidin-2-amine 925-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-2-methoxypyrimidine 935-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-N-methylpyrimidin-2-amine 945-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-N-(2,2,2-trifluoroethyl)pyrimidin-2-amine 953-(3-Chlorophenyl)-2-methoxy-5-(1,2-oxazol-4-ylmethyl)pyrazine 963-(3-Chlorophenyl)-2-methoxy-5-(1,2-oxazol-4-ylmethyl)pyridine 973-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1,2-oxazol-4-ylmethyl)pyridine983-(3-Chlorophenyl)-5-[(dimethyl-1,2-oxazol-4-yl)methyl]-2-methoxypyrazine99 3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(dimethyl-1,2-oxazol-4-yl)methyl]pyridine 100 Methyl2-(4-{[5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}phenyl)acetate 101 Ethyl1-(4-{[5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}phenyl)cyclopropane-1-carboxylate 1023-(3-Chlorophenyl)-5-{[6-(cyclopropylmethoxy)pyridin-3-yl]methyl}-2-(difluoromethoxy)pyridine 1035-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyridine-2-carbonitrile 1045-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyrimidin-2-amine 1055-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}pyrimidin-2-amine 1065-({6-[3-(Difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)pyrimidin-2-amine 1075-({6-[3-(Difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)pyrimidine-2-carbonitrile 1085-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}pyrimidine-2-carbonitrile1093-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(pyridin-2-ylmethyl)pyridine1102-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyrazine1116-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridazin-3-amine 1123-(3-Chlorophenyl)-2-methoxy-6-methyl-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine113 4-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}benzamide 1145-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridine-2-carboxamide 1155-{[6-(Difluoromethoxy)-5-(3-methoxyphenyl)pyridin-3-yl]methyl}pyrimidine-2-carboxamide 1165-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridine-2-carboxamide1175-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyrimidine-2-carboxamide 1185-{[5-(3-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxamide1195-({5-[3-(Difluoromethoxy)phenyl]-6-ethoxypyridin-3-yl}methyl)pyrimidine-2-carboxamide 1205-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)pyrimidine-2-carboxamide 1215-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)pyrimidine-2-carboxamide 1225-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-ethoxypyridin-3-yl}methyl)pyrimidine-2-carboxamide 1235-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}pyrimidine-2-carboxamide 1245-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyridine-2-carboxamide 1255-({6-[3-(Difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)pyrimidine-2-carboxamide 1265-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}pyrimidine-2-carboxamide127 Methyl1-{[6-(3-chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-1,2,4-triazole-3-carboxylate 1283-(3-Chlorophenyl)-5-[(3-cyclopropyl-1H-1,2,4-triazol-1-yl)methyl]-2-(difluoromethoxy)pyridine 1293-(3-Fluorophenyl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine 1303-(3-Chlorophenyl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyrazine 1313-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine132 3-(3-Chlorophenyl)-2-methoxy-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyrazine 1333-(3-Chlorophenyl)-5-[(3-cyclopropyl-1H-1,2,4-triazol-1-yl)methyl]-2-methoxypyrazine 1343-(3-Chlorophenyl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine 1353-(3-Chlorophenyl)-2-(propan-2-yloxy)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine1363-[2-Methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridin-3-yl]benzonitrile137 2-Methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)-3-[3-(trifluoromethoxy)phenyl]pyridine 1383-(3-Chlorophenyl)-2-methoxy-5-[(3-methyl-4H-1,2,4-triazol-4-yl)methyl]pyridine 1393-(3,5-Difluorophenyl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine140 Methyl1-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazole-5-carboxylate 141 Methyl1-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazole-3-carboxylate 1423-(4-Chlorothiophen-2-yl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine143 3-(3-Chlorophenyl)-2-methoxy-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyridine 1443-[3-(Difluoromethyl)phenyl]-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine145 3-(3-Chlorophenyl)-2-methoxy-5-(1H-pyrazol-1-ylmethyl)pyridine 1463-(3-Chlorophenyl)-2-methoxy-5-{[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine 1473-(3-Chlorophenyl)-5-[(3-cyclopropyl-1H-1,2,4-triazol-1-yl)methyl]-2-methoxypyridine 1483-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyridine 1493-(3-Chlorophenyl)-2-methoxy-5-{[4-(trifluoromethyl)-1H-imidazol-1-yl]methyl}pyridine 1503-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[1-(1H-1,2,4-triazol-1-yl)ethyl]pyridine 1513-(3-Fluorophenyl)-2-methoxy-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyridine1523-(3-Chlorophenyl)-2-ethoxy-5-{[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine 1533-(3-Chlorophenyl)-2-ethoxy-5-{[5-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine 1543-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(4-methyl-1H-imidazol-1-yl)methyl]pyridine 1553-[3-(Difluoromethoxy)phenyl]-2-methoxy-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyridine 1561-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-1,2,4-triazole-3-carbonitrile 1573-(3-Chlorophenyl)-2-(difluoromethoxy)-5-{[3-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine 1583-(3-Chlorophenyl)-2-(difluoromethoxy)-5-{[5-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine 1593-[3-(Difluoromethoxy)phenyl]-2-methoxy-5-{[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine 1603-[3-(Difluoromethoxy)phenyl]-2-methoxy-5-{[5-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine 1613-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1H-1,2,3,4-tetrazol-1-ylmethyl)pyridine 1623-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(2H-1,2,3,4-tetrazol-2-ylmethyl)pyridine 1633-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine 1643-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[5-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine 1653-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[3-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine 1663-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[5-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine 1675-[(4-Chloro-1H-pyrazol-1-yl)methyl]-3-[3-(difluoromethoxy)phenyl]-2-methoxypyridine 1681-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazole-3-carboxamide 169 Ethyl1-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-4-carboxylate 1701-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-4-carbonitrile 1712-Methoxy-3-(pyridin-4-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine 172N-(1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazol-4-yl)acetamide 1733-(3-Chlorophenyl)-5-(1H-imidazol-1-ylmethyl)-2-methoxypyridine 1742-(Difluoromethoxy)-3-(3-fluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine175 2-(Difluoromethoxy)-3-(3-methoxyphenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine 1762-(Difluoromethoxy)-5-(1H-1,2,4-triazol-1-ylmethyl)-3-[3-(trifluoromethoxy)phenyl]pyridine 1771-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1,2-dihydropyridin-2-one1785-[(4-Chloro-1H-pyrazol-1-yl)methyl]-3-(3-chlorophenyl)-2-methoxypyridine1793-(3-Chlorophenyl)-2-methoxy-5-[(4-methyl-1H-pyrazol-1-yl)methyl]pyridine1803-(3-Chlorophenyl)-2-methoxy-5-[(4-nitro-1H-pyrazol-1-yl)methyl]pyridine1813-(3-Chlorophenyl)-2-methoxy-5-[(4-nitro-1H-pyrazol-1-yl)methyl]pyrazine182 3-(3-Chlorophenyl)-2-methoxy-5-(1H-pyrazol-1-ylmethyl)pyrazine 1833-(3-Chlorophenyl)-5-(1H-imidazol-1-ylmethyl)-2-methoxypyrazine 1843-(3-Chlorophenyl)-2-methoxy-5-[(4-methyl-1H-pyrazol-1-yl)methyl]pyrazine1853-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyrazine 1865-[(3-Cyclopropyl-1H-1,2,4-triazol-1-yl)methyl]-3-[3-(difluoromethoxy)phenyl]-2-ethoxypyrazine 1873-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyrazine 1883-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[5-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyrazine 1893-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[3-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyrazine 1903-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[5-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyrazine 191 Methyl1-((6-(3-(difluoromethoxy)phenyl)-5-ethoxypyrazin-2-yl)methyl)-1H-1,2,4-triazole-3-carboxylate 192 Methyl1-((6-(3-(difluoromethoxy)phenyl)-5-ethoxypyrazin-2-yl)methyl)-1H-1,2,4-triazole-5-carboxylate 1933-(3-(Difluoromethoxy)phenyl)-2-ethoxy-5-((3-nitro-1H-1,2,4-triazol-1-yl)methyl)pyrazine 1943-(3-(Difluoromethoxy)phenyl)-2-ethoxy-5-((5-nitro-1H-1,2,4-triazol-1-yl)methyl)pyrazine 195 Methyl1-{[6-(3-chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-1,2,4-triazole-5-carboxylate 196 Methyl1-({6-[3-(difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)-1H-1,2,4-triazole-3-carboxylate 197 Methyl1-{[6-(3-chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-1H-1,2,4-triazole-3-carboxylate 1981-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-imidazole-4-carboxamide 199(1-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol 200(1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol 201[1-({5-[3-(Difluoromethoxy)phenyl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol 202[1-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol 203(1-((5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl)methyl)-1H-1,2,4-triazol-3-yl)methanol 204(1-{[6-(Difluoromethoxy)-5-(3-ethoxyphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol 205[1-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)-1H-l,2,4-triazol-3-yl]methanol 206[1-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol 207(1-{[6-(Difluoromethoxy)-5-[2-(difluoromethoxy)pyridin-4-yl]pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol 208[1-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol 209[1-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)-1H-1,2,4-triazol-5-yl]methanol 210(1-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-1,2,4-triazol-5-yl)methanol 211[1-({6-[3-(Difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol 212(1-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol 2133-(3-Chlorophenyl)-2-methoxy-5-[(3-methoxy-1H-1,2,4-triazol-1-yl)methyl]pyridine 2143-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(3-methoxy-1H-1,2,4-triazol-1-yl)methyl]pyridine 2153-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(5-methoxy-1H-1,2,4-triazol-1-yl)methyl]pyridine 2163-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(3-ethoxy-1H-1,2,4-triazol-1-yl)methyl]pyridine 2171-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-amine 2181-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine2191-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine 2201-{[5-(3-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine2211-{[6-Methoxy-5-(3-methoxyphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine 2221-{[6-Methoxy-5-(3-methylphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine223 3-{5-[(3-Amino-1H-1,2,4-triazol-1-yl)methyl]-2-methoxypyridin-3-yl}benzonitrile 2241-{[5-(3-Ethoxyphenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine2251-{[5-(3-Cyclopropoxyphenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine 2261-({5-[3-(Difluoromethoxy)phenyl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-amine 2271-{[6-(Difluoromethoxy)-5-(3-methoxyphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine 2281-{[5-(5-Chloropyridin-3-yl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine 2291-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-amine 2301-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-amine 2311-{[6-(Difluoromethoxy)-5-[2-(difluoromethoxy)pyridin-4-yl]pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine 2321-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-pyrazol-3-amine 2331-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-pyrazol-5-amine 2344-Chloro-1-{[5-(3-chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazol-3-amine 2354-Chloro-1-{[5-(3-chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazol-5-amine 2361-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-pyrazol-4-amine2371-((6-(3-(Difluoromethoxy)phenyl)-5-ethoxypyrazin-2-yl)methyl)-1H-1,2,4-triazol-3-amine 2381-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-N-methyl-1H-1,2,4-triazol-3-amine 2391-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-N,N-dimethyl-1H-1,2,4-triazol-3-amine 240(1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanamine 2411-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazole-3-carboxamide 2422-Methoxy-3-(1H-pyrazol-4-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine243 4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N-(oxetan-3-yl)benzamide 2445-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-N-methylpyridine-2-carboxamide 2451-(4-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}phenyl)cyclopropane-1-carboxamide 2462-(4-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}phenyl)acetamide 2472-(1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)propan-2-ol 2482-Methoxy-3-(1-methyl-1H-pyrazol-4-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine2492-(1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-5-yl)propan-2-ol 2502-(4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)propan-2-ol2512-(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridin-2-yl)propan-2-ol 2522-(5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridin-2-yl)propan-2-ol 2533-[3-(Difluoromethoxy)phenyl]-5-{[3-(fluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}-2-methoxypyridine 2543-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[4-(fluoromethyl)-1H-1,2,3-triazol-1-yl]methyl}pyridine 2552-(Difluoromethoxy)-3-(3-ethoxyphenyl)-5-{[3-(fluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine 2563-[2-(Difluoromethoxy)pyridin-4-yl]-5-{[3-(fluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}-2-methoxypyridine 2573-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[3-(fluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyrazine 2583-(3-Chlorophenyl)-5-{[3-(fluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}-2-methoxypyrazine 2593-(3-Chlorophenyl)-2-(difluoromethoxy)-5-{[3-(difluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine 2603-[3-(Difluoromethoxy)phenyl]-5-{[3-(difluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}-2-ethoxypyridine 2613-[2-(Difluoromethoxy)pyridin-4-yl]-5-{[3-(difluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}-2-methoxypyridine 2623-(3-Chlorophenyl)-2-methoxy-5-(1H-1,2,3-triazol-1-ylmethyl)pyridine 263[1-({5-[3-(Difluoromethoxy)phenyl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,3-triazol-4-yl]methanol 264(1-((6-(Difluoromethoxy)-5-(3-ethoxyphenyl)pyridin-3-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol 265[1-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)-1H-1,2,3-triazol-4-yl]methanol 266(1-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-1,2,3-triazol-4-yl)methanol 267[1-({6-[3-(Difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)-1H-1,2,3-triazol-4-yl]methanol 268(1-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-1H-1,2,3-triazol-4-yl)methanol 2693-[3-(Difluoromethoxy)phenyl]-5-{[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]methyl}-2-ethoxypyridine 2701-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-4-carboxylicacid 2711-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-4-carboxamide 272[1-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-pyrazol-4-yl]methanol 273(1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-imidazol-5-yl)methanol 274(1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-imidazol-4-yl)methanol 275[1-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-pyrazol-3-yl]methanol 276(1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazol-4-yl)methanol277(4-Chloro-1-{[5-(3-chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazol-3-yl)methanol 278(4-Chloro-1-{[5-(3-chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazol-5-yl)methanol 2793-(4-Chloro-1H-pyrazol-1-yl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine2804-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}benzoicacidIsotopically-Labeled Compounds

The invention also includes isotopically-labeled compounds, which areidentical to those recited in Formula I, but for the fact that one ormore atoms are replaced by an atom having an atomic mass or mass numberdifferent from the atomic mass or mass number usually found in nature.Examples of isotopes that can be incorporated into compounds of theinvention include isotopes of carbon, chlorine, fluorine, hydrogen,iodine, nitrogen, oxygen, phosphorous, sulfur, and technetium, including¹¹C, ¹³C, ¹⁴C, ³⁶Cl, ¹⁸F, ²H, ³H, ¹²³I, ¹²⁵I, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O,³¹P, ³²P, ³⁵S, and ^(99m)Tc.

Compounds of the present invention (and derivatives of such compounds,such as pharmaceutically acceptable salts and prodrugs) that contain theaforementioned isotopes or other isotopes of other atoms are within thescope of the invention. Isotopically-labeled compounds of the presentinvention are useful in drug and substrate tissue distribution andtarget occupancy assays. For example, isotopically labeled compounds areparticularly useful in SPECT (single photon emission computedtomography) and in PET (positron emission tomography), as discussedfurther herein.

Derivatives

The present invention also provides derivatives of a chemical entity ofFormula (I), which include, but are not limited to, any salt, solvate,conformer, crystalline or formpolymorph.

Salts

Accordingly, in one embodiment the invention includes pharmaceuticallyacceptable salts of the compounds represented by Formula (I), andmethods using such salts.

Examples of pharmaceutically acceptable salts include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, phosphates,monohydrogen-phosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates, borate, nitrate,propionates, decanoates, caprylates, acrylates, formates, is obutyrates,caproates, heptanoates, propiolates, oxalates, malonates, succinates,suberates, sebacates, fumarates, maleates, butyne-1,4-dioates,hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates,sulfonates, xylenesulfonates, phenylacetates, phenylpropionates,phenylbutyrates, citrates, lactates, y-hydroxybutyrates, glycolates,tartrates, methane-sulfonates, propane sulfonates,naphthalene-1-sulfonates, naphthalene-2-sulfonates, besylate, mesylateand mandelates.

When the compound of Formula (I) contains a basic nitrogen, the desiredpharmaceutically acceptable salt may be prepared by any suitable methodavailable in the art, for example, treatment of the free base with aninorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuricacid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and thelike, or with an organic acid, such as acetic acid, phenylacetic acid,propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid,hydroxymaleic acid, isethionic acid, succinic acid, valeric acid,fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid,salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidylacid, such as glucuronic acid or galacturonic acid, an alpha-hydroxyacid, such as mandelic acid, citric acid, or tartaric acid, an aminoacid, such as aspartic acid, glutaric acid or glutamic acid, an aromaticacid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, orcinnamic acid, a sulfonic acid, such as laurylsulfonic acid,p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, anycompatible mixture of acids such as those given as examples herein, andany other acid and mixture thereof that are regarded as equivalents oracceptable substitutes in light of the ordinary level of skill in thistechnology.

When the compound of Formula (I) is an acid, such as a carboxylic acidor sulfonic acid, the desired pharmaceutically acceptable salt may beprepared by any suitable method, for example, treatment of the free acidwith an inorganic or organic base, such as an amine (primary, secondaryor tertiary), an alkali metal hydroxide, alkaline earth metal hydroxide,any compatible mixture of bases such as those given as examples herein,and any other base and mixture thereof that are regarded as equivalentsor acceptable substitutes in light of the ordinary level of skill inthis technology. Illustrative examples of suitable salts include organicsalts derived from amino acids, such as N-methyl-O-glucamine, lysine,choline, glycine and arginine, ammonia, carbonates, bicarbonates,primary, secondary, and tertiary amines, and cyclic amines, such astromethamine, benzylamines, pyrrolidines, piperidine, morpholine, andpiperazine, and inorganic salts derived from sodium, calcium, potassium,magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

Solvates

In other embodiments, the invention provides a solvate of a compound ofFormula (I), and the use of such solvates in methods of presentinvention. Certain compounds of Formula (I) or pharmaceuticallyacceptable salts of compounds of Formula (I) may be obtained assolvates. In some embodiments, the solvent is water and the solvates arehydrates.

More particularly, solvates include those formed from the interaction orcomplexes of compounds of the invention with one or more solvents,either in solution or as a solid or crystalline form. Such solventmolecules are those commonly used in the pharmaceutical art, which areknown to be innocuous to the recipient, e.g., water, ethanol, ethyleneglycol, and the like. Other solvents may be used as intermediatesolvates in the preparation of more desirable solvates, such as MeOH,methyl t-butyl ether, ethyl acetate, methyl acetate, (S)-propyleneglycol, (R)-propylene glycol, 1,4-butyne-diol, and the like. Hydratesinclude compounds formed by an incorporation of one or more watermolecules.

Conformers and Crystalline Forms/Polymorphs

In other embodiments, the invention provides conformer and crystallineform of a compound of Formula (I), and the use of these derivatives inmethods of present invention. A conformer is a structure that is aconformational isomer. Conformational isomerism is the phenomenon ofmolecules with the same structural formula but different conformations(conformers) of atoms about a rotating bond.

A polymorph is a composition having the same chemical formula, but adifferent solid state or crystal structure. In certain embodiments ofthe invention, compounds of Formula (I) were obtained in crystallineform. In addition, certain crystalline forms of compounds of Formula (I)or pharmaceutically acceptable salts of compounds of Formula (I) may beobtained as co-crystals. In still other embodiments, compounds ofFormula (I) may be obtained in one of several polymorphic forms, as amixture of crystalline forms, as a polymorphic form, or as an amorphousform.

Prodrugs

The invention also relates to prodrugs of the compounds of Formula (I),and the use of such pharmaceutically acceptable prodrugs in methods ofthe present invention, particularly therapeutic methods. Exemplaryprodrugs include compounds having an amino acid residue, or apolypeptide chain of two or more (e.g., two, three or four) amino acidresidues, covalently joined through an amide or ester bond to a freeamino, hydroxy, or carboxylic acid group of a compound of Formula (I).Examples of amino acid residues include the twenty naturally occurringamino acids, commonly designated by three letter symbols, as well as4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline homocysteine, homoserine, ornithine and methionine sulfone.

Additional types of prodrugs may be produced, for instance, byderivatizing free carboxyl groups of structures of Formula (I) as amidesor alkyl esters. Examples of amides include those derived from ammonia,primary C₁₋₆alkyl amines and secondary di(C₁₋₆alkyl) amines. Secondaryamines include 5- or 6-membered heterocycloalkyl or heteroaryl ringmoieties. Examples of amides include those that are derived fromammonia, C₁₋₃ alkyl primary amines, and di(C₁₋₂alkyl)amines. Examples ofesters of the invention include C₁₋₆alkyl, C₁₋₆cycloalkyl, phenyl, andphenyl(C₁₋₆alkyl) esters. Preferred esters include methyl esters.Prodrugs may also be prepared by derivatizing free hydroxy groups usinggroups including hemisuccinates, phosphate esters,dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, followingprocedures such as those outlined in Fleisher et al., Adv. Drug DeliveryRev. 1996, 19, 115-130.

Carbamate derivatives of hydroxy and amino groups may also yieldprodrugs. Carbonate derivatives, sulfonate esters, and sulfate esters ofhydroxy groups may also provide prodrugs. Derivatization of hydroxygroups as (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acylgroup may be an alkyl ester, optionally substituted with one or moreether, amine, or carboxylic acid functionalities, or where the acylgroup is an amino acid ester as described above, is also useful to yieldprodrugs. Prodrugs of this type may be prepared as described in Robinsonet al., J. Med. Chem. 1996, 39, 10-18. Free amines can also bederivatized as amides, sulfonamides or phosphonamides. All of theseprodrug moieties may incorporate groups including ether, amine, andcarboxylic acid functionalities.

Prodrugs may be determined using routine techniques known or availablein the art (e.g., Bundgard (ed.), 1985, Design of prodrugs, Elsevier;Krogsgaard-Larsen et al., (eds.), 1991, Design and Application ofProdrugs, Harwood Academic Publishers).

Metabolites

The present invention also relates to a metabolite of a compound ofFormula (I), as defined herein, and salts thereof. The present inventionfurther relates to the use of such metabolites, and salts thereof, inmethods of present invention, including therapeutic methods.

Metabolites of a compound may be determined using routine techniquesknown or available in the art. For example, isolated metabolites can beenzymatically and synthetically produced (e.g., Bertolini et al., J.Med. Chem. 1997, 40, 2011-2016; Shan et al., J. Pharm. Sci. 1997, 86,765-767; Bagshawe, Drug Dev. Res. 1995, 34, 220-230; and Bodor, Adv DrugRes. 1984, 13, 224-231).

Compositions

In some embodiments compounds of Formula (I) and pharmaceuticallyacceptable salts thereof are used, alone or in combination with one ormore additional active ingredients, to formulate pharmaceuticalcompositions. A pharmaceutical composition of the invention comprises:(a) an effective amount of at least one active agent in accordance withthe invention; and (b) a pharmaceutically acceptable excipient.

Formulations and Administration

Numerous standard references are available that describe procedures forpreparing various formulations suitable for administering the compoundsaccording to the invention. Examples of potential formulations andpreparations are contained, for example, in the Handbook ofPharmaceutical Excipients, American Pharmaceutical Association (currentedition); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman andSchwartz, editors) current edition, published by Marcel Dekker, Inc., aswell as Remington's Pharmaceutical Sciences (Osol, ed.), 1980,1553-1593.

Any suitable route of administration may be employed for providing ananimal, especially a human, with an effective dosage of a compound ofthe present invention. For example, oral, rectal, topical, parenteral,ocular, pulmonary, nasal, and the like may be employed. Dosage formsinclude tablets, troches, dispersions, suspensions, solutions, capsules,creams, ointments, aerosols, and the like.

Suitable carriers, diluents and excipients are well known to thoseskilled in the art and include materials such as carbohydrates, waxes,water soluble and/or swellable polymers, hydrophilic or hydrophobicmaterials, gelatin, oils, solvents, water, and the like. The particularcarrier, diluent, or excipient used will depend upon the means andpurpose for which the compound of the present invention is beingapplied. Solvents are generally selected based on solvents recognized bypersons skilled in the art as safe (GRAS) to be administered to ananimal. In general, safe solvents are non-toxic aqueous solvents such aswater and other non-toxic solvents that are soluble or miscible inwater. Suitable aqueous solvents include water, ethanol, propyleneglycol, polyethylene glycols (e.g., PEG400, PEG300), etc. and mixturesthereof. The formulations may also include one or more buffers,stabilizing agents, surfactants, wetting agents, lubricating agents,emulsifiers, suspending agents, preservatives, antioxidants, opaquingagents, glidants, processing aids, colorants, sweeteners, perfumingagents, flavoring agents and other known additives to provide an elegantpresentation of the drug (i.e., a compound of the present invention orpharmaceutical composition thereof) or aid in the manufacturing of thepharmaceutical product (i.e., medicament).

The formulations may be prepared using conventional dissolution andmixing procedures. For example, the bulk drug substance (i.e., acompound of the present invention or stabilized form of the compound(e.g., complex with a cyclodextrin derivative or other knowncomplexation agent)) is dissolved in a suitable solvent in the presenceof one or more of the excipients described above. The compound of thepresent invention is typically formulated into pharmaceutical dosageforms to provide an easily controllable and appropriate dosage of thedrug.

The pharmaceutical composition (or formulation) for application may bepackaged in a variety of ways, depending upon the method used toadminister the drug. Generally, an article for distribution includes acontainer having deposited therein the pharmaceutical formulation in anappropriate form. Suitable containers are well-known to those skilled inthe art and include materials such as bottles (plastic and glass),sachets, ampoules, plastic bags, metal cylinders, and the like. Thecontainer may also include a tamper-proof assemblage to preventindiscreet access to the contents of the package. In addition, thecontainer has deposited thereon a label that describes the contents ofthe container. The label may also include appropriate warnings.

The present compounds may be systemically administered, e.g., orally, incombination with a pharmaceutically acceptable vehicle such as an inertdiluent or an assimilable edible carrier. They may be enclosed in hardor soft shell gelatin capsules, may be compressed into tablets, or maybe incorporated directly with the food of the patient's diet. For oraltherapeutic administration, the active compound may be combined with oneor more excipients and used in the form of ingestible tablets, buccaltablets, troches, capsules, elixirs, suspensions, syrups, wafers, andthe like. Such compositions and preparations should contain at least0.1% of active compound. The percentage of the compositions andpreparations may, of course, be varied and may conveniently be betweenabout 2 to about 60% of the weight of a given unit dosage form. Theamount of active compound in such therapeutically useful compositions issuch that an effective dosage level will be obtained.

The tablets, troches, pills, capsules, and the like may also contain thefollowing: binders such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, fructose, lactose or aspartame or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring may be added. Whenthe unit dosage form is a capsule, it may contain, in addition tomaterials of the above type, a liquid carrier, such as a vegetable oilor a polyethylene glycol. Various other materials may be present ascoatings or to otherwise modify the physical form of the solid unitdosage form. For instance, tablets, pills, or capsules may be coatedwith gelatin, wax, shellac or sugar and the like. A syrup or elixir maycontain the active compound, sucrose or fructose as a sweetening agent,methyl and propylparabens as preservatives, a dye and flavoring such ascherry or orange flavor. Of course, any material used in preparing anyunit dosage form should be pharmaceutically acceptable and substantiallynon-toxic in the amounts employed. In addition, the active compound maybe incorporated into sustained-release preparations and devices.

The active compound may also be administered intravenously orintraperitoneally by infusion or injection. Solutions of the activecompound or its salts can be prepared in water, optionally mixed with anontoxic surfactant. Dispersions can also be prepared in glycerol,liquid polyethylene glycols, triacetin, and mixtures thereof and inoils. Under ordinary conditions of storage and use, these preparationscontain a preservative to prevent the growth of microorganisms.

The pharmaceutical dosage forms suitable for injection or infusion caninclude sterile aqueous solutions or dispersions or sterile powderscomprising the active ingredient which are adapted for theextemporaneous preparation of sterile injectable or infusible solutionsor dispersions, optionally encapsulated in liposomes. In all cases, theultimate dosage form should be sterile, fluid, and stable under theconditions of manufacture and storage. The liquid carrier or vehicle canbe a solvent or liquid dispersion medium comprising, for example, water,ethanol, a polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycols, and the like), vegetable oils, nontoxic glycerylesters, and suitable mixtures thereof. The proper fluidity can bemaintained, for example, by the formation of liposomes, by themaintenance of the required particle size in the case of dispersions orby the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, buffers or sodiumchloride. Prolonged absorption of the injectable compositions can bebrought about by the use in the compositions of agents delayingabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are typically prepared by incorporating theactive compound in the required amount in the appropriate solvent with avariety of the other ingredients enumerated above, as required, followedby filter sterilization. In the case of sterile powders for thepreparation of sterile injectable solutions, common methods ofpreparation are vacuum drying and the freeze drying techniques, whichyield a powder of the active ingredient plus any additional desiredingredient present in the previously sterile-filtered solutions.

For topical administration, the present compounds may be applied in pureform, i.e., when they are liquids. However, it will generally bedesirable to administer them to the skin as compositions orformulations, in combination with a dermatologically acceptable carrier,which may be a solid or a liquid.

Useful solid carriers include finely divided solids such as talc, clay,microcrystalline cellulose, silica, alumina, and the like. Useful liquidcarriers include water, alcohols or glycols or water-alcoholglycolblends, in which the present compounds can be dissolved or dispersed ateffective levels, optionally with the aid of non-toxic surfactants.Adjuvants such as fragrances and additional antimicrobial agents can beadded to optimize the properties for a given use. The resultant liquidcompositions can be applied from absorbent pads, used to impregnatebandages and other dressings, or sprayed onto the affected area usingpump-type or aerosol sprayers.

Thickeners such as synthetic polymers, fatty acids, fatty acid salts andesters, fatty alcohols, modified celluloses or modified mineralmaterials can also be employed with liquid carriers to form spreadablepastes, gels, ointments, soaps, and the like, for application directlyto the skin of the user.

Dosages

Useful dosages of the compounds of Formula (I) can be determined bycomparing their in vitro activity and in vivo activity in animal models.Methods for the extrapolation of effective dosages in mice, and otheranimals, to humans are known to the art. Useful dosages of the compoundsof formula I can be determined by comparing their in vitro activity, andin vivo activity in animal models. Methods for the extrapolation ofeffective dosages in mice, and other animals, to humans are known to theart (e.g., U.S. Pat. No. 4,938,949). Useful dosages of PDE4 inhibitorsare known to the art (e.g., U.S. Pat. No. 7,829,713; U.S. Pat. No.8,338,405).

Optimal dosages to be administered in the therapeutic methods of thepresent invention may be determined by those skilled in the art and willdepend on multiple factors, including the particular composition in use,the strength of the preparation, the mode and time of administration,and the advancement of the disease or condition. Additional factors mayinclude characteristics on the subject being treated, such as age,weight, gender, and diet.

In general, however, a suitable dose will be in the range from about0.01 to about 100 mg/kg, more specifically from about 0.1 to about 100mg/kg, such as 10 to about 75 mg/kg of body weight per day, 3 to about50 mg per kilogram body weight of the recipient per day, 0.5 to 90mg/kg/day, or 1 to 60 mg/kg/day (or any other value or range of valuestherein). The compound is conveniently administered in a unit dosageform; for example, containing about 1 to 1000 mg, particularly about 10to 750 mg, and more particularly, about 50 to 500 mg of activeingredient per unit dosage form.

Preferably, the active ingredient should be administered to achieve peakplasma concentrations of the active compound of from about 0.5 to about75 μM, preferably, about 1 to 50 μM, and more preferably, about 2 toabout 30 μM. This may be achieved, for example, by the intravenousinjection of a 0.05 to 5% solution of the active ingredient, optionallyin saline, or orally administered as a bolus containing about 1 to 100mg of the active ingredient. Desirable blood levels may be maintained bycontinuous infusion to provide about 0.01 to 5.0 mg/kg/hr or byintermittent infusions containing about 0.4 to 15 mg/kg of the activeingredient(s).

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of temporally-distinctadministrations used according to the compositions and methods of thepresent invention.

Effective amounts or doses of the active agents of the present inventionmay be ascertained by routine methods such as modeling, dose escalationstudies or clinical trials, and by taking into consideration routinefactors, e.g., the mode or route of administration or drug delivery, thepharmacokinetics of the agent, the severity and course of the disease,disorder, or condition, the subject's previous or ongoing therapy, thesubject's health status and response to drugs, and the judgment of thetreating physician. Such compositions and preparations should contain atleast 0.1% of active compound. The percentage of the compositions andpreparations may, of course, be varied and may conveniently be between 2to about 60% of the weight of a given unit dosage form. The amount ofactive compound in such therapeutically useful composition is such thatan effective dosage level will be obtained. An exemplary dose is in therange from about 0.001 to about 200 mg of active agent per kg ofsubject's body weight per day, preferably about 0.05 to 100 mg/kg/day,or about 1 to 35 mg/kg/day, or about 0.1 to 10 mg/kg/daily in single ordivided dosage units (e.g., BID, TID, QID). For a 70-kg human, anillustrative range for a suitable dosage amount is from 1 to 200 mg/day,or about 5 to 50 mg/day.

Methods and Uses

Uses of Isotopically-Labeled Compounds

In one aspect, the present invention provides a method of usingisotopically labeled compounds and prodrugs of the present invention in:(i) metabolic studies (preferably with ¹⁴C), reaction kinetic studies(with, for example ²H or ³H); (ii) detection or imaging techniques [suchas positron emission tomography (PET) or single-photon emission computedtomography (SPECT)] including drug or substrate tissue distributionassays; or (iii) in radioactive treatment of patients.

Isotopically labeled compounds and prodrugs of the invention thereof cangenerally be prepared by carrying out the procedures disclosed in theschemes or in the examples and preparations described below bysubstituting a readily available isotopically labeled reagent for anon-isotopically labeled reagent. An ¹⁸F or ¹¹C labeled compound may beparticularly preferred for PET, and an I¹²³ labeled compound may beparticularly preferred for SPECT studies. Further substitution withheavier isotopes such as deuterium (i.e., ²H) may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life or reduced dosage requirements.

Therapeutic Methods

Generally

In certain embodiments the present invention provides therapeuticmethods of using a compound of Formula (I) and its pharmaceuticallyacceptable salts, pharmaceutically acceptable prodrugs, andpharmaceutically active metabolites, whether alone or in combination(collectively, “active agents”) of the present invention are useful asinhibiting PDE4 in the methods of the invention. Such methods forinhibiting PDE4 comprising administering to an animal an effectiveamount of at least one chemical entity selected from compounds ofFormula (I), pharmaceutically acceptable salts of compounds of Formula(I), pharmaceutically acceptable prodrugs of compounds of Formula (I),and pharmaceutically active metabolites of compounds of Formula (I).Embodiments of this invention inhibit PDE4. The invention furtherincludes the use compositions of such chemical entities in the methodsdescribed herein. In one aspect of such methods disclosed herein, theanimal is healthy. In another aspect of such methods, the animal has adisorder. In another aspect of all such methods the animal is an agedanimal. In preferred embodiments of such methods, the animal is a human.

Chemical entities of the present invention may be administered as amono-therapy or as part of a combination therapy. In one aspect, one ormore of the compounds (or salts, produgs, or metabolites thereof) of thepresent invention may be co-administered or used in combination with oneor more additional therapies known in the art.

Compounds of the present invention may also be used as adjunct therapy,for example, with other PDE inhibitors.

The present invention also includes methods of treating a disease,disorder, or condition mediated by PDE4. Accordingly, in one embodiment,the invention provides a method of treating a disorder mediated by PDE4in particular, comprising administering to an animal in need of suchtreatment an effective amount of a chemical entity of Formula (I) orcomposition of the present invention.

In certain embodiments, the present invention includes the use of achemical entity of Formula (I) in the manufacture of a medicament fortreating a disease, condition, or disorder by inhibiting PDE4 Thepresent invention further provides a method of administering atherapeutically effective amount of a medicament of the presentinvention to a patient in need of such treatment to treat the disorder.

In one aspect, the compounds of the present invention are useful inenhancing neuronal plasticity—an essential property of the brain thatcan be augmented in healthy animals and can be impaired in numerous CNSdisorders. For example, by inhibiting PDE4, a compound of the presentinvention can increase levels of cAMP, modulating cyclic nucleotidesignaling cascades.

More particularly, the ability of extracellular signals to modulate theintracellular concentration of cyclic nucleotides allows cells torespond to external stimuli across the boundary of the cell membrane.The cyclic nucleotide signaling cascades have been adapted to respond toa host of transduction systems including G-protein coupled receptors(GPCRs) and voltage and ligand gated ion channels. Cyclic nucleotidestransmit their signal in the cell through a variant of tertiaryelements. The best described of these are cAMP dependent protein kinase(PKA) and cGMP dependent protein kinase (PKG). The binding of the cyclicnucleotide to each enzyme enables the phosphorylation of downstreamenzymes and proteins functioning as effectors or additional elements inthe signaling cascade. Of particular importance to memory formation iscAMP-dependent activation of PKA, which phosphorylates CREB. pCREB is anactivated transcription factor, which binds to specific DNA loci andinitiates transcription of multiple genes involved in neuronalplasticity (e.g., Tully et al., Nat. Rev. Drug. Discov. 2003, 2,267-277; and Alberini, Physiol. Rev. 2009, 89, 121-145).

Consistent with these observations, both in vitro and in vivo studieshave associated alterations in cyclic nucleotide concentrations withbiochemical and physiological process linked to cognitive function(Kelly and Brandon, Progress in Brain Research, 2009, 179, 67-73;Schmidt, Current Topics in Medicinal Chemistry, 2010, 10, 222-230).Moreover, signal intensity and the levels of coincident activity at asynapse are established variables that can result in potentiation oftransmission at a particular synapse. Long term potentiation (LTP) isthe best described of these processes and is known to be modulated byboth the cAMP and cGMP signaling cascades.

Accordingly, the present invention provides a method of enhancingneuronal plasticity, comprising administering to an animal in needthereof an effective amount of a chemical entity or composition of thepresent invention.

In another embodiment, the present invention provides a method oftreating a disease mediated by PDE4, comprising administering to ananimal in need of such treatment an effective amount of a compound orcomposition of the present invention. PDE4-related indications that canbe treated by compounds and compositions of the present inventioninclude, but are not limited to neurological disorders, inflammatorydisorder, renal disorder, and other disorders involving PDE4.

Chemical entities and compositions of the present invention are alsouseful as neuroprotective agents, as described in greater detail herein.Accordingly, the present invention provides a method of neuroprotection,comprising administering to an animal in need thereof an effectiveamount of at least one chemical entity or composition of the presentinvention.

Chemical entities and compositions of the present invention are alsouseful as agents in neurorehabilitation and neurorecovery, as describedin greater detail herein. Accordingly, the present invention provides amethod of neurorehabilitation or neurorecovery, comprising administeringto an animal in need thereof an effective amount of at least onechemical entity or composition of the present invention.

In addition, such compounds can be administered in conjunction withtraining protocols to treat cognitive or motor deficits associated withCNS disorders, as described in more detail herein. In addition, suchcompounds can be used to enhance the efficiency of training protocols innon-human animals, in particular healthy non-human animals, as describedherein.

Neurological Disorders

In some embodiments, the present invention provides a method of treatinga neurological disorder, comprising administering to an animal in needof such treatment an effective amount of a compound or compositiondescribed herein.

A neurological disorder (or condition or disease) is any disorder of thebody's nervous system. Neurological disorders can be categorizedaccording to the primary location affected, the primary type ofdysfunction involved, or the primary type of cause. The broadestdivision is between central nervous system (CNS) disorders andperipheral nervous system (PNS) disorders.

Neurological disorders include structural, biochemical, or electricalabnormalities in the brain, spinal cord or other nerves, abnormalitiesthat can result in a range of symptoms. Examples of such symptomsinclude paralysis, muscle weakness, poor coordination, loss ofsensation, seizures, confusion, pain, altered levels of consciousness,and cognitive deficits, including memory impairments. There are manyrecognized neurological disorders, some relatively common, but manyrare. They may be assessed by neurological examination, and studied andtreated within the specialties of neurology and clinicalneuropsychology.

Neurological disorders and their sequelae (direct consequences) affectas many as one billion people worldwide, as estimated by the WorldHealth Organization in 2006. Interventions for neurological disordersmay include, in addition to medications, preventative measures,lifestyle changes, physiotherapy or other therapies,neurorehabilitation, pain management, and surgery.

Neurological disorders include, but are not limited to the following(which are not necessarily mutually exclusive): psychiatric disorders,such as mood disorders, psychotic disorders, and anxiety disorders;personality disorders; substance-related disorders; dissociativedisorders; eating disorders; sleep disorders; developmental disorders;neurodegenerative disorders, including movement disorders;trauma-related disorders; pain disorders; and cognitive disorders, acategory that includes memory disorders such as AAMI and MCI, as well ascognitive deficits (particularly memory deficits) associated with CNSdisorders.

Psychiatric Disorders

In one embodiment, the invention provides a method of treating apsychiatric disorder, comprising administering to an animal in need ofsuch treatment an effective amount of a compound or pharmaceuticalcomposition described herein. Psychiatric disorders include mood (oraffective) disorders, psychotic disorders, and anxiety (or neurotic)disorders.

Mood Disorders

In some embodiments, the psychiatric disorder is a mood (or affective)disorder. Accordingly, the present invention provides a method oftreating a mood disorder, comprising administering to an animal in needof such treatment an effective amount of a compound or pharmaceuticalcomposition described herein. In a specific aspect, the mood disorder isa depressive disorder, including a dysthymic disorder, major depressivedisorder (recurrent and single episode), mania, bipolar disorders (I andII), and cyclothymic disorder. Long-standing research underscores a rolefor PDE4 in mood disorders, including depressive disorders, bipolardisorders, and substance induced mood disorders is known in theliterature.

A specific embodiment of the invention is a method of treating asubstance induced mood disorder, comprising administering to an animalin need of such treatment a therapeutically effective amount of acompound or pharmaceutical composition described herein. The utility ofPDE4 inhibitors in the treatment of substance induced mood disorders isknown in the literature.

Psychotic Disorders

In some embodiments, the psychiatric disorder is a psychotic disorder.Accordingly, the present invention provides a method of treating apsychotic disorder, comprising an animal in need of such treatment aneffective amount of a compound or pharmaceutical composition describedherein. In a specific aspect, the psychotic disorder is one or more ofthe following: schizophrenia; schizophreniform disorder; schizoaffectivedisorder; delusional disorder; brief psychotic disorder; sharedpsychotic disorder; substance-induced psychotic disorders, such as apsychosis induced by alcohol, amphetamine, cannabis, cocaine,hallucinogens, inhalants, opioids, or phencyclidine; and personalitydisorders at times of stress (including paranoid personality disorder,schizoid personality disorder, and borderline personality disorder).

A specific embodiment of the invention is a method of treating adelusional disorder, comprising administering to an animal in need ofsuch treatment a therapeutically effective amount of a compound orpharmaceutical composition described herein. The utility of PDE4inhibitors in the treatment of delusional disorders is known in theliterature.

A particular embodiment of the invention is a method of treatingschizophrenia, comprising administering to an animal in need of suchtreatment a therapeutically effective amount of a compound orpharmaceutical composition described herein. The utility of PDE4inhibitors in the treatment of schizophrenia, including schizophreniformdisorder and schizoaffective disorder, is known in the literature.

Anxiety Disorders

In some embodiments, the psychiatric disorder is an anxiety (orneurotic) disorder. Accordingly, the present invention provides a methodof treating an anxiety disorder, comprising administering to an animalin need of such treatment an effective amount of a compound orpharmaceutical composition described herein. More particularly, theanxiety disorder is one or more of the following: panic disorder,specific phobia, social phobia, obsessive-compulsive disorder,generalized anxiety disorder, post-traumatic stress disorder; and acutestress disorder. The use of PDE4 inhibitors in the treatment of anxietyis known in the literature.

Personality Disorders

In some embodiments, the neurological disorder is a personalitydisorder. Accordingly, the present invention provides a method oftreating a personality disorder, comprising administering to an animalin need of such treatment an effective amount of a compound orpharmaceutical composition described herein. In particular embodiments,the personality disorder is one or more of the following: includes thoseof Cluster A (odd or eccentric), such as paranoid or schizoidpersonality disorder; those of Cluster B (dramatic, emotional, orerratic), such as antisocial, borderline, or narcissistic personalitydisorder; and those of Cluster C (anxious or fearful), such as avoidant,dependent, or obsessive-compulsive personality disorder.

Substance Related Disorders

In some embodiments, the neurological disorder is a substance-relateddisorder. Accordingly, a specific embodiment of the invention is amethod of treating a substance-related disorder, comprisingadministering to an animal in need of such treatment an effective amountof a compound or pharmaceutical composition described herein.

More particularly, the substance-related disorder includes one or moreof the following: an alcohol-related disorder, such as abuse,dependence, and withdrawal; an amphetamine (or amphetamine-related)disorder, such as abuse, dependence and withdrawal, a cocaine-relateddisorder, such as abuse, dependence and withdrawal; ahallucinogen-related disorder, such as abuse, dependence and withdrawal;an inhalant-related disorder, such as dependent and withdrawal; anicotine-related disorder, such as dependence and withdrawal; anopioid-related disorder, such as abuse, dependence and withdrawal; aphencyclidine (or phencyclidine-like) related disorder, such as abuseand dependence; and a sedative-, hypnotic-, or anxiolytic-relateddisorder, such as abuse, dependence, and withdrawal.

In a specific embodiment, the compounds and compositions of the presentinvention are useful as an aid to a treatment of smoking cessation.Accordingly, the present invention provides a method of treating smokingaddiction, comprising administering to an animal in need thereof aneffective amount of a compound or composition of the present invention.

Dissociative Disorders

In some embodiments, the neurological disorder is a dissociativedisorder. Accordingly, a specific embodiment of the invention is amethod of treating a dissociative disorder, comprising administering toan animal in need of such treatment an effective amount of a compound orpharmaceutical composition described herein. More particularly, thedissociative disorder includes one or more of the following:depersonalization disorder, dissociative amnesia, and dissociativeidentity disorder.

Eating Disorders

In some embodiments, the neurological disorder is an eating disorder.Accordingly, a specific embodiment of the invention is a method oftreating an eating disorder, comprising administering to an animal inneed of such treatment an effective amount of a compound orpharmaceutical composition described herein. More particularly, theeating disorder is anorexia nervosa or bulimia nervosa. The utility ofPDE4 inhibitors in the treatment of eating disorders is known in theliterature.

Sleep Disorders

In some embodiments, the neurological disorder is a sleep disorder.Accordingly, a specific embodiment of the invention is a method oftreating a sleep disorder, comprising administering to an animal in needof such treatment an effective amount of a compound or pharmaceuticalcomposition described herein. More particularly, the sleep disorderincludes a primary sleep disorder, such as primary hypersomnia, primaryinsomnia, and narcolepsy; a parasomnia, such as a nightmare or sleeptenor disorder; and other sleep disorders. The utility of PDE4inhibitors in the treatment of sleep disorders is known in theliterature.

In other embodiments, the sleep disorder is restless leg syndrome.Restless legs syndrome (RLS) is a disorder of the part of the nervoussystem that affects the legs and causes an urge to move them. Peoplewith restless legs syndrome have uncomfortable sensations in their legs(and sometimes arms or other parts of the body) and an irresistible urgeto move their legs to relieve the sensations. The sensations are usuallyworse at rest, especially when lying or sitting. The sensations can leadto sleep deprivation and stress. Because it usually interferes withsleep, it also is considered a sleep disorder. Accordingly, the presentinvention provides a method of treating restless leg syndrome,comprising administering to an animal in need thereof an effectiveamount of a compound or composition of the present invention.

Developmental Disorders

In some embodiments, the neurological disorder is a developmentaldisorder. Accordingly, a specific embodiment of the invention is amethod of treating a developmental disorder, comprising administering toan animal in need of such treatment an effective amount of a compound orpharmaceutical composition described herein.

More particularly, the developmental disorder is one or more of thefollowing: mental retardation, including mild, moderate, and severeforms; a learning disorder, such as that affecting reading, mathematics,or written expression; a motor skill disorder, such as developmentalcoordination disorder; a communication disorder; a pervasivedevelopmental disorder, such as an autistic disorder, Rhett's disorder,childhood disintegrative disorder, and Asperger's disorder; anattention-deficit or disruptive disorder, such as attention-deficithyperactivity disorder; and a tic disorder, such as Tourette's disorder,chronic motor disorder, or vocal tic disorder.

A specific embodiment of the invention is a method of treating anautistic disorder, comprising administering to an animal in need of suchtreatment an effective amount of a compound or pharmaceuticalcomposition described herein. In another embodiment, the inventionprovides a method of treating an attention-deficit hyperactivitydisorder, comprising administering to an animal in need of suchtreatment a therapeutically effective amount of a compound orpharmaceutical composition described herein. The utility of PDE4inhibitors in the treatment of attention-deficit hyperactivity disorderis known in the literature.

Neurodegenerative Disorders

In particular embodiments, the invention provides a method of treating aneurodegenerative disorder, comprising administering to an animal inneed of such treatment an effective amount of a compound orpharmaceutical composition described herein.

In one aspect, neurodegenerative disorders include Alzheimer's disease,Amyotrophic lateral sclerosis, corticobasal degeneration, chronictraumatic encephalopathy, and a disorder associated with repetitive headinjury.

Alzheimer's Disease

In a specific embodiment, the invention provides a method of treatingAlzheimer's disease, comprising administering to an animal in need ofsuch treatment an effective amount of a compound or pharmaceuticalcomposition described herein. A detailed set of criteria for thediagnosis of Alzheimer's is set forth in the Diagnostic and StatisticalManual of Mental Disorders (Fourth Edition, text revision (2000), alsoknown as the DSM-IV-TR). First, multiple cognitive deficits must bepresent, one of which must be memory impairment. Second, one or more ofthe following must be present: aphasia (deterioration of languageabilities); apraxia (difficulty executing motor activities even thoughmovement, senses, and the ability to understand what is being asked arestill intact); or agnosia (impaired ability to recognize or identifyobjects even though sensory abilities are intact).

Amyotrophic Lateral Sclerosis

In another specific embodiment, the invention provides a method oftreating amyotrophic lateral sclerosis, comprising administering to ananimal in need of such treatment an effective amount of a compound orpharmaceutical composition described herein.

Amyotrophic lateral sclerosis (ALS), often referred to as “Lou Gehrig'sDisease,” is a progressive neurodegenerative disease that affects nervecells. Motor neurons reach from the brain to the spinal cord and fromthe spinal cord to the muscles throughout the body. As motor neuronsdegenerate, they can no longer send impulses to the muscle fibers thatnormally result in muscle movement.

Early symptoms of ALS often include increasing muscle weakness,especially involving the arms and legs, speech, swallowing or breathing.The progressive degeneration of the motor neurons in ALS eventuallyleads to their death. When the motor neurons die, the ability of thebrain to initiate and control muscle movement is lost. With voluntarymuscle action progressively affected, patients in the later stages ofthe disease may become totally paralyzed.

Movement Disorders

In other embodiments, the invention provides a method of treating amovement disorder, comprising administering to an animal in need of suchtreatment an effective amount of a compound or pharmaceuticalcomposition described herein. In one aspect, the movement disorderincludes one or more of the following: Huntington's disease, Parkinson'sdisease, an essential tremor, a Lewy body disease, hypokinetic disease,Multiple Sclerosis, various types of Peripheral Neuropathy, dystonia, abasal ganglia disorder, hypokinesia (including akinesia), anddyskinesia. In addition, Tourette's syndrome and other tic disorders canbe included as categories of movement disorders. The utility of PDE4inhibitors in the treatment of movement disorders is known in theliterature.

In related embodiment, the invention provides a method of treatingchorea, comprising administering to an animal in need of such treatmentan effective amount of a compound or pharmaceutical compositiondescribed herein. Chorea can occur in a variety of conditions anddisorders, and is a primary feature of Huntington's disease, aprogressive neurological disorder.

Huntington's Disease

In a specific embodiment, the present invention provides a method oftreating Huntington's disease, comprising administering to an animal inneed of such treatment an effective amount of a compound orpharmaceutical composition described herein.

Huntington's Disease (HD, or Huntington chorea) is a disorder passeddown through families in which nerve cells in certain parts of the brainwaste away, or degenerate. It is caused by a genetic defect onchromosome 4, causing a CAG repeat, to occur many more times thannormal. The CAG element is normally repeated 10 to 28 times, but inpersons with Huntington's disease, is repeated 36 to 120 times.

There are two forms of Huntington's disease: adult-onset Huntington'sdisease which is the most common form and usually begins in the mid 30sand 40s; and early-onset Huntington's disease, which accounts for asmall number of cases and begins in childhood or adolescence.

Symptoms of Huntington's disease include behavioral changes, abnormaland unusual movements, and worsening dementia. Behavioral changes mayinclude behavioral disturbances, hallucinations, irritability,moodiness, restlessness or fidgeting, paranoia, and psychosis. Abnormaland unusual movements include facial movements, such as grimaces; headturning to shift eye position; quick, sudden, sometimes wild jerkingmovements of the arms, legs, face, and other body parts; slow,uncontrolled movements; and unsteady gait. Worsening dementia includes;disorientation or confusion; loss of judgment; loss of memory;personality changes; and speech changes (e.g., Dumas et al., “A reviewof cognition in Huntington's disease”, Front Biosci (Schol Ed) 2013, 5,1-18). The utility of PDE4 inhibitors in treating Huntington's diseaseis known in the art.

Parkinson's Disease

In a specific embodiment, the present invention provides a method oftreating Parkinson's disease, comprising administering to an animal inneed of such treatment an effective amount of a compound orpharmaceutical composition described herein.

In another embodiment, the invention provides a method of treatingmyoclonus, Gilles de Ia Tourette's syndrome, dystonia, or tics,comprising administering to an animal in need of such treatment aneffective amount of a compound or pharmaceutical composition describedherein. The utility of PDE4 inhibitors in the treatment of myoclonus,Tourette's syndrome, dystonia and tics is known in the art.

In a specific aspect, a movement disorder also includes multiplesclerosis, basal ganglia disorders, hypokinesia, and dyskinesia.

Lewy Body Diseases

In one embodiment, the present embodiment, the invention provides amethod of treating a Lewy Body Disease, comprising administering to ananimal in need of such treatment an effective amount of a compound orcomposition of the present invention. Lewy bodies appear as sphericalmasses that displace other cell components. The two morphological typesare classical (brain stem) Lewy bodies and cortical Lewy bodies. Aclassical Lewy body is an eosinophilic cytoplasmic inclusion consistingof a dense core surrounded by a halo of 10-nm-wide radiating fibrils,the primary structural component of which is alpha-synuclein. Incontrast, a cortical Lewy body is less well defined and lacks the halo.Nonetheless, it is still made up of alpha-synuclein fibrils. CorticalLewy bodies are a distinguishing feature of Dementia with Lewy bodies(DLB), but may occasionally be seen in ballooned neurons characteristicof Pick's disease and corticobasal degeneration, as well as in patientswith other tauopathies.

More particularly, the Lewy Body disorder is selected from the groupconsisting of multiple system atrophy, particularly the Parkinsonianvariant; Parkinson disease without or with dementia (PDD); dementia withLBs (DLB) alone or in association with Alzheimer disease (AD); multiplesystem atrophy, particularly the Parkinsonian variant, as well as Pick'sdisease and corticobasal degeneration.

Multiple Sclerosis

In one embodiment, the present invention provides a method of treating amotor symptom associated with multiple sclerosis (MS), comprisingadministering to animal in need of such treatment an effective amount ofa compound or composition of the present invention. MS is an autoimmune,demyelinating disease that affects the brain and spinal cord of the CNS.It affects women more than men and is most commonly diagnosed betweenages 20 and 40, but can be seen at any age.

MS is caused by damage to the myelin sheath, the protective coveringthat surrounds nerve cells. When this nerve covering is damaged, nervesignals slow down or stop. Because nerves in any part of the brain orspinal cord may be damaged, patients with multiple sclerosis can havesymptoms in many parts of the body. Symptoms vary, because the locationand severity of each attack can be different. Episodes can last fordays, weeks, or months. These episodes alternate with periods of reducedor no symptoms (remissions).

Muscle symptoms associated with MS include loss of balance; musclespasms; numbness, tingling, or abnormal sensation in any area; problemsmoving arms or legs; problems walking; problems with coordination andmaking small movements; tremor in one or more arms or legs; and weaknessin one or more arms or legs.

Basal Ganglia Disorders

In particular embodiments, the present invention provides a method oftreating a basal ganglia disorder. Basal ganglia disorders refer to agroup of physical dysfunctions that occur when the group of nuclei inthe brain known as the basal ganglia fail to properly suppress unwantedmovements or to properly prime upper motor neuron circuits to initiatemotor function (Leisman and Mello, Rev. Neurosci. 2013, 24, 9-25).

Increased output of the basal ganglia inhibits thalamocorticalprojection neurons. Proper activation or deactivation of these neuronsis an integral component for proper movement. If something causes toomuch basal ganglia output, then the thalamocortical projection neuronsbecome too inhibited and one cannot initiate voluntary movement. Thesedisorders are known as hypokinetic disorders. However, a disorderleading to abnormally low output of the basal ganglia leads torelatively no inhibition of the thalamocortical projection neurons. Thissituation leads to an inability to suppress unwanted movements. Thesedisorders are known as hyperkinetic disorders (Wichmann and DeLong,Curr. Opin. Neurobiol 1996, 6, 751-758).

Hypokinesia

In particular embodiments, the present invention provides a method oftreating hypokinesia. Hypokinesia refers to decreased bodily movements,and they may be associated with basal ganglia diseases (such asParkinson's disease), mental health disorders and prolonged inactivitydue to illness, amongst other diseases.

More generally, hypokinesia describes a spectrum of disorders,including: (i) Akinesia, which refers to the inability to initiatemovement due to difficulty selecting or activating motor programs in thecentral nervous system. Akinesia is a result of severely diminisheddopaminergic cell activity in the direct pathway of movement and iscommon in severe cases of Parkinson's disease; (ii) Bradykinesia, whichis characterized by slowness of movement and has been linked toParkinson's disease and other disorders of the basal ganglia. Ratherthan being a slowness in initiation (akinesia), bradykinesia describes aslowness in the execution of movement. It is one of the 3 key symptomsof parkinsonism, which are bradykinesia, tremor and rigidity.Bradykinesia is also the cause of what is normally referred to as “stoneface” (expressionless face) among those with Parkinson's; (iii)Freezing, which is characterized by an inability to move muscles in anydesired direction; and (iv) Rigidity, which is characterized by anincrease in muscle tone causing resistance to externally imposed jointmovements; and (v) Postural instability, which is the loss of ability tomaintain an upright posture.

Dyskinesia

In particular embodiments, the present invention provides a method oftreating dyskinesia. Dyskinesia is a movement disorder which consists ofadverse effects including diminished voluntary movements and thepresence of involuntary movements, similar to tics or chorea.

Dyskinesia can be anything from a slight tremor of the hands touncontrollable movement of, most commonly, the upper body but can alsobe seen in the lower extremities. Discoordination can also occurinternally especially with the respiratory muscles and it often goesunrecognized. Dyskinesia is a symptom of several medical disorders,distinguished by the underlying cause and generally corresponding to oneof three types: acute dyskinesia, chronic (or tardive) dyskinesia, andnon-motor dyskinesia.

More specifically, a dyskinesia can include one or more the following:paroxysmal dyskinesias, e.g., primary and secondary paroxysmaldyskinesias; paroxysmal kinesigenic dyskinesias (PKD); paroxysmalnon-kinesigenic dyskinesias (PNKD); paroxysmal exercise-induced(exertion-induced) dyskinesias (PED); and paroxysmal hypnogenicdyskinesias (PHD).

Trauma-Related Disorders

In specific embodiments, the present invention provides a method oftreating a trauma-related disorder, comprising administering to ananimal in need of such treatment an effective amount of a compound orpharmaceutical composition of the present invention.

In specific embodiments, trauma-related disorders comprise brain trauma;head trauma (closed and penetrating); head injury; tumors, especiallycerebral tumors affecting the thalamic or temporal lobe head injuries;cerebrovascular disorders (diseases affecting the blood vessels in thebrain), such as stroke, ischemia, hypoxia, and viral infection (e.g.,encephalitis); excitotoxicity; and seizures.

Conditions within the scope of the invention that are amenable toneuroprotection include: Stroke; traumatic brain injury (TB); Dementia;Alzheimer's disease; Parkinson's disease; Huntington's disease; Cerebralpalsy; Post-polio syndrome; Guillain-Barre syndrome, and MultipleSclerosis; and other developmental syndromes, genetic conditions, andprogressive CNS diseases affecting cognitive function, such as autismspectrum disorders, fetal alcohol spectrum disorders (FASD),Rubinstein-Taybi syndrome, Down syndrome, and other forms of mentalretardation.

Pain Disorders

In specific embodiments, the invention provides methods of treatingpain, comprising administering to an animal in need of such treatment aneffective amount of a compound or pharmaceutical composition describedherein. The utility of PDE4 inhibitors in the treatment of pain is knownin the literature.

In particular embodiments, the pain disorder includes one or more of thefollowing: dental pain, cancer pain, myofascial pain, perioperativepain, acute pain, chronic pain, posttraumatic pain, trigeminalneuralgia, migraine severe pain, intractable pain, neuropathic pain,post-traumatic pain, cancer pain, non-cancer pain. Pain also encompassesa pain disorder associated with psychological factors, a pain disorderassociated with a general medical condition, and a pain disorderassociated with both psychological factors and a general medicalcondition.

Cognitive Disorders

In particular embodiments of the invention, the neurological disorder isa cognitive disorder. Accordingly, the present invention provides amethod of treating a cognitive disorder, comprising administering to ananimal in need of such treatment an effective amount of a compound orpharmaceutical composition described herein. The utility of PDE4inhibitors in the treatment of cognitive disorders is known in theliterature (e.g., U.S. Pat. No. 7,829,713; U.S. Pat. No. 8,338,405).

Cognitive disorders can significantly impair social and occupationalfunctioning, adversely impacting the autonomy and quality of life of theaffected individual. An estimated four to five million Americans (about2% of all ages and 15% of those older than 65) have some form and degreeof cognitive impairment (Abrams et al., Merck Manual of Geriatrics,1995, Whitehouse Station (NJ), Medical Services).

Cognitive disorders reflect problems in cognition, i.e., the generalprocesses by which knowledge is acquired, retained and used.Accordingly, cognitive disorders can encompass impairments in suchfunctions as concentration, perception, attention, informationprocessing, learning, memory, or language. Cognitive disorders can alsoencompass impairments in psychomotor learning abilities, which includephysical skills, such as movement and coordination; fine motor skillssuch as the use of precision instruments or tools; and gross motorskills, such as dance, musical, or athletic performance.

Cognitive disorders also encompass impairments in executive functions,which include abilities underlying the planning and execution ofgoal-oriented behaviors. Such abilities include flexibility, i.e., thecapacity for quickly switching to the appropriate mental mode;anticipation and prediction based on pattern recognition; reasoning andproblem-solving; decision making; working memory, i.e., the capacity tohold and manipulate internally- or externally-derived information inreal time; emotional self-regulation, including the ability to recognizeand manage one's emotions for good performance; sequencing, such as theability to dissect complex actions into manageable units and prioritizethem in the right order; and self-inhibition, i.e., the ability towithstand distraction and internal urges.

Cognitive disorders also comprise cognitive impairments (deficits ordysfunctions) that are associated with (due to) to CNS disorders. In oneaspect, a cognitive impairment can be a direct result of a CNS disorder.For example, impairments in speech and language can directly result froma stroke or head-injury that damages the brain regions controllingspeech and language, as in aphasia.

In another aspect, a cognitive impairment is associated with a complexCNS disorder, condition, or disease. For example, a cognitive impairmentcan comprise a deficit in executive control that accompanies autism ormental retardation; a deficit in memory associated with schizophrenia orParkinson's disease; or a cognitive deficit arising from multiplesclerosis. In the case of multiple sclerosis (MS), for example, aboutone-half of MS patients will experience problems with cognitivefunction, such as slowed thinking, decreased concentration, or impairedmemory. Such problems typically occur later in the course of MS—althoughin some cases they can occur much earlier, if not at the onset ofdisease.

Cognitive impairments can be due to many, non-exclusive categories ofCNS disorders, including the following (and as described herein):

-   -   (1) dementias, such as those associated with Alzheimer's        disease, Parkinson's disease; Huntington's disease, Pick's        disease, Creutzfeldt-Jakob, AIDS Dementia, and other        neurodegenerative disorders; and cognitive disabilities        associated with progressive diseases involving the nervous        system, such as multiple sclerosis.    -   (2) psychiatric disorders, which include affective (mood)        disorders, such as depression and bipolar disorders; psychotic        disorders, such as schizophrenia and delusional disorder; and        neurotic and anxiety disorders, such as phobias, panic        disorders, obsessive-compulsive disorder, generalized anxiety        disorder; eating disorders; and posttraumatic stress disorders.    -   (3) developmental syndromes, genetic conditions, and progressive        CNS diseases affecting cognitive function, such as autism        spectrum disorders; fetal alcohol spectrum disorders (FASD);        Rubinstein-Taybi syndrome; Down syndrome, and other forms of        mental retardation; and multiple sclerosis.    -   (4) trauma-dependent losses of cognitive functions, i.e.,        impairments in memory, language, or motor skills resulting from        brain trauma; head trauma (closed and penetrating); head injury;        tumors, especially cerebral tumors affecting the thalamic or        temporal lobe; cerebrovascular disorders (diseases affecting the        blood vessels in the brain), such as stroke, ischemia, hypoxia,        and viral infection (e.g., encephalitis); excitotoxicity; and        seizures. Such trauma-dependent losses also encompass cognitive        impairments resulting from extrinsic agents such as alcohol use,        long-term drug use, and neurotoxins, e.g., lead, mercury, carbon        monoxide, and certain insecticides (e.g., Duncan et al.,        “Monoamine oxidases in major depressive disorder and        alcoholism”, Drug Discover. Ther. 2012, 6, 112-122).    -   (5) age-associated cognitive deficits, including age-associated        memory impairment (AAMI; also referred to herein as age-related        memory impairment (AMI)), and deficits affecting patients in        early stages of cognitive decline, as in Mild Cognitive        Impairment (MCI); and    -   (6) learning, language, or reading disabilities, such as        perceptual handicaps, dyslexia, and attention deficit disorders.

Accordingly, the invention provides a method of treating a cognitiveimpairment associated with a CNS disorder selected from one or more ofthe group comprising: dementias, including those associated withneurodegenerative disorders; psychiatric disorders; developmentalsyndromes, genetic conditions, and progressive CNS diseases and geneticconditions; trauma-dependent losses of cognitive function,age-associated cognitive deficits; and learning, language, or readingdisorders.

Dementias

In a specific embodiment, the invention provides a method of treating acognitive deficit associated with dementia, comprising administering toan animal in need of such treatment an effective amount of a compound orpharmaceutical composition described herein.

Dementias are neurodegenerative diseases characterized by learning andcognitive deficiencies and are typically accompanied by behavioralsymptoms, psychological symptoms and motor symptoms. More particularly,dementia symptoms can include difficulty with many areas of mentalfunction, including emotional behavior or personality, language, memory,perception, and thinking and judgment.

Dementias include, but are not limited to, the following: dementia dueto Alzheimer's disease (with early or late onset), dementia due toParkinson's disease, dementia due to Pick's disease, dementia due toCreutzfeldt-Jakob disease, dementia due to HIV disease, dementia due tohead trauma; dementia due to a vascular disease (“vascular dementia”),Lewy body dementia, fronto-temporal dementia, Pick's disease andcorticobasal degeneration.

In one embodiment, dementia is due to Alzheimer's disease. Accordingly,the present invention provides a method of treating dementia due toAlzheimer's disease, comprising administering to an animal in need ofsuch treatment a therapeutically effective amount of a compound orpharmaceutical composition described herein. The utility of PDE4inhibitors in the treatment of Alzheimer's disease is known in theliterature. Accordingly, the invention provides a method of treatingdementia due to Alzheimer's disease, comprising administering to ananimal in need of such treatment a therapeutically effective amount of acompound or pharmaceutical composition described herein.

In another embodiment, dementia is due to Parkinson's disease.Accordingly, the invention provides a method of treating dementia due toParkinson's disease, comprising administering to an animal in need ofsuch treatment a therapeutically effective amount of a compound orpharmaceutical composition described herein. Dementia has been reportedto occur in approximately 20%-60% of individuals with Parkinson'sdisease and is more likely to be present in older individuals or thosewith more severe or advanced disease. The dementia associated withParkinson's disease is characterized by cognitive and motoric slowing;problems with executive functioning, such as planning tasks, organizingprojects, or carrying out goals in the proper sequence; and impairmentin memory retrieval. Declining cognitive performance in individuals withParkinson's disease is frequently exacerbated by depression. The utilityof PDE4 inhibitors in treating Parkinson's disease is known in theliterature.

Dementia has been reported to occur in approximately 20%-60% ofindividuals with Parkinson's disease and is more likely to be present inolder individuals or those with more severe or advanced disease. Thedementia associated with Parkinson's disease is characterized bycognitive and motoric slowing, executive dysfunction, and impairment inmemory retrieval. Declining cognitive performance in individuals withParkinson's disease is frequently exacerbated by depression. For areview, Davie, “A review of Parkinson's disease”, Br. Med. Bull. 2008,86, 109-127. The motor symptoms of Parkinson's disease result from thedeath of dopamine-generating cells in the substantia nigra, a region ofthe midbrain; the cause of this cell death is unknown. Early in thecourse of the disease, the most obvious symptoms are movement-related.Four motor symptoms are considered cardinal in PD: shaking (tremors),rigidity, slowness of movement, and postural instability, i.e.,difficulty with walking and gait (e.g., Jankovic, “Parkinson's disease:clinical features and diagnosis”, J. Neurol. Neurosurg. Psychiatr. 2008,79, 368-376). Later, cognitive and behavioral problems may arise, withdementia commonly occurring in the advanced stages of the disease. Othersymptoms include sensory, sleep and emotional problems. PD is morecommon in the elderly, with most cases occurring after the age of 50.

In another aspect, a cognitive impairment is associated with a complexCNS syndrome, condition, or disease. For example, a cognitive impairmentcan comprise a deficit in executive control that accompanies autism ormental retardation; a deficit in memory associated with schizophrenia orParkinson's disease; or a cognitive deficit arising from multiplesclerosis. In the case of multiple sclerosis (MS), for example, aboutone-half of MS patients will experience problems with cognitivefunction, such as slowed thinking, decreased concentration, or impairedmemory. Such problems typically occur later in the course of MS althoughin some cases they can occur much earlier, if not at the onset ofdisease.

In one aspect, a cognitive impairment can be a direct result of a CNSdisorder. For example, impairments in speech and language can directlyresult from a stroke or head-injury that damages the brain regionscontrolling speech and language, as in aphasia.

Psychiatric Disorders

In a specific embodiment, the invention provides a method of treating acognitive deficit associated with a psychiatric disorder, comprisingadministering to an animal in need of such treatment an effective amountof a compound or pharmaceutical composition described herein.Psychiatric disorders include affective disorders (mood disorders), suchas depression and bipolar disorders; psychotic disorders, such asschizophrenia and delusional disorder; and neurotic and anxietydisorders, such as phobias, panic disorders, obsessive-compulsivedisorder, generalized anxiety disorder, eating disorders, andposttraumatic stress disorders.

Developmental Syndromes, Genetic Disorders, and Progressive Diseases

In a specific embodiment, the invention provides a method of treating acognitive deficit associated with a developmental syndrome, geneticdisorder, or progressive disease, comprising administering to an animalin need of such treatment an effective amount of a compound orpharmaceutical composition described herein. In a specific aspect, thecognitive deficit is associated with an autism spectrum disorder; afetal alcohol spectrum disorder (FASD); Rubinstein-Taybi syndrome; Downsyndrome, and other forms of mental retardation; and multiple sclerosis.

Trauma-Related Disorders

In a specific embodiment, the invention provides a method of treating acognitive deficit associated with trauma. Such trauma-dependent lossesof cognitive function include, but are not limited to, those due tocerebrovascular diseases, including stroke and ischemia; brain trauma,including subdural hematoma and brain tumor; traumatic brain injury(TBI) and head injury.

Such trauma-dependent losses also encompass cognitive impairmentsresulting from extrinsic agents such as alcohol use, long-term drug use,and neurotoxins such as lead, mercury, carbon monoxide, and certaininsecticides.

Age-Associated Cognitive Deficits

AAMI

In a specific embodiment, the invention provides a method of treating anage-associated cognitive deficit. In one aspect, the age-associatedcognitive deficit is age-related memory impairment (AAMI). Accordingly,the invention provides a method of treating age-associated memoryimpairment (AAMI), comprising administering to an animal in need of suchtreatment an effective amount of a compound or pharmaceuticalcomposition described herein.

AAMI is a decline in various cognitive abilities, in particular memoryabilities, associated with normal aging. For example, AAMI subjects showa decline in the ability to encode new memories of events or facts, aswell as working memory (Hedden and Gabrieli, “Insights into the agingmind: a view from cognitive neuroscience”, Nat. Rev. Neurosci. 2004, 5,87-96). In addition, AAMI subjects, when compared with age-matchedcontrols, appeared to be impaired in tests of executive functionsassociated with frontal lobe function. These and other studies suggestan important role for frontal lobe dysfunction in the memory loss ofelderly people. (More generally, studies comparing the effects of agingon episodic memory, semantic memory, short-term memory and priming findthat episodic memory is especially impaired in normal aging; but sometypes of short-term memory can also be impaired (Nilsson, “Memoryfunction in normal aging”, Acta Neurol. Scand. Suppl. 2003, 179, 7-13)

In general, an AAMI diagnosis identifies persons with subjectively andobjectively evidenced memory loss without cognitive decline impairedenough to warrant the diagnosis of dementia. According to criteriaestablished by the NIH working group (Crook et al., “Age-associatedmemory impairment: proposed diagnostic criteria and measures of clinicaldamage report of a National Institute of Mental Health work group”,Devel. Neuropsychol. 1986, 2, 261-276) a diagnosis of AAMI includes thefollowing in a person aged 50 or older:

-   -   (i) the presence of subjective memory decline, e.g., complaints        of memory loss reflected in such everyday problems as difficulty        remembering names of individuals introduced to the subject,        misplacing objects, difficulty remembering a list of items to be        purchased or a list of tasks to be performed;    -   (ii) objective evidence of memory loss (e.g., a score at least        one standard deviation below the mean of younger adults in a        well standardized memory test);    -   (iii) evidence of adequate intellectual function (e.g., a raw        score of at least 32) on the Vocabulary subtest of the Wechsler        Adult Intelligence Scale., and    -   (iv) the absence of dementia (or other memory-affecting disease,        such as stroke), e.g., based on the Global Deterioration Scale        for assessment of dementia, individuals with AAMI have very mild        cognitive decline (level 2) (Reisberg et al., “The global        deterioration Scale for assessment of primary degenerative        dementia”, Am. J. Psych. 1982, 139, 1136-1139).

Individuals with AAMI have been shown to have a three-fold greater riskfor development of dementia than individuals who do not meet AAMIcriteria (Goldman and Morris, “Evidence that age-associated memoryimpairment is not a normal variant of aging” Alzheimer Dis. Assoc.Disord. 2002, 15:72-79).

MCI

In a specific embodiment, the invention provides a method of treatingmild cognitive impairment (MCI), comprising administering to an animalin need of such treatment an effective amount of a compound orpharmaceutical composition described herein.

MCI may be diagnosed when an individual's memory declines below thelevel considered normal for that age group. In other words, MCI is acondition in which people face memory problems more often than that ofthe average person their age. These symptoms, however, do not preventthem from carrying out normal activities and are not as severe as thesymptoms for Alzheimer's disease. Symptoms often include misplacingitems, forgetting events or appointments, and having trouble thinking ofdesired words.

According to recent research, MCI has been called the transitional statebetween cognitive changes of normal aging and Alzheimer's disease (AD).Many people who experience mild cognitive impairment are at a high riskof developing Alzheimer's disease. Indeed, research suggests that: about12% of people aged 65 or older diagnosed with MCI go on to developAlzheimer's disease within a year; and that about 40% developAlzheimer's within three years. This is a much higher rate than in thegeneral population, wherein only about 1% of people aged 65 or olderdevelop Alzheimer's each year.

Thus, people with MCI are considered at heightened risk to developAlzheimer's disease. These symptoms, however, do not prevent them fromcarrying out normal activities and are not as severe as the symptoms forAlzheimer's disease. Symptoms often include misplacing items, forgettingevents or appointments, and having trouble thinking of desired words(e.g., Arnaiz and Almkvist, “Neuropsychological features of mildcognitive impairment and preclinical Alzheimer's disease” Acta Neurol.Scand. Suppl. 2003, 179, 34-41). Some patients with MCI, however, neverprogress to AD.

Learning and Related Disabilities

In a specific embodiment, the invention provides a method of treating alearning, language, or reading disability, comprising administering toan animal in need of such treatment an effective amount of a compound orpharmaceutical composition described herein.

Neuroprotection

In specific embodiments, the invention provides a method ofneuroprotection, comprising administering to animal in need thereof aneffective amount of a chemical entity or composition of the presentinvention.

Like neuroplasticity, neuroprotection reflects an endogenousneurobiological process that is central to protection of the nervoussystem. More specifically, neuroprotection refers to the ability to haltor slow the loss of neurons, thereby preventing or slowing diseaseprogression and secondary injuries. In a particular aspect,neuroprotection targets neuronal damage arising from oxidative stressand excitotoxicity both of which are highly associated with CNSdisorders, despite differences in symptoms or injuries.

The utility of PDE4 inhibitors in the treatment of neuronal damage isknown in the literature. In addition to neurodegenerative diseases,neuronal damage can also result from other sources of trauma, such ascerebrovascular diseases, including stroke and ischemia; brain trauma,including subdural hematoma and brain tumor; and head injury.

Augmented Cognitive and Motor Training

In certain embodiments, a compound or composition herein is used as anaugmenting agent in methods to enhance the efficiency of cognitive ormotor training (collectively “training”). Such enhancement methods arecollectively known as “augmented training,” comprising “augmentedcognitive training” or “augmented motor training.”

Training generally requires multiple sessions to attain the desiredbenefits, for example, to rehabilitate a motor deficit or languagedeficit following stroke. This can be costly and time-consuming,deterring subject compliance and the realization of real world benefitsthat endure over time. The efficiency of such training protocols can beimproved by administering certain agents (known as augmenting agents) inconjunction with the training protocol (e.g., U.S. Pat. No. 7,868,015;U.S. Pat. No. 7,947,731; US 2008-0188525). Augmented training comprisesa specific training protocol for a particular brain function, such asthat underlying declarative memory, performance of a fine motor skill,locomotion, language acquisition, an executive function, etc., and ageneral administration of CREB pathway-enhancing drugs. The trainingprotocol (cognitive or motor training) induces neuronal activity inspecific brain regions and produces improved performance of a specificbrain (cognitive or motor) function.

In some embodiments, the invention provides methods of treating acognitive disorder, and more particularly, methods for improving acognitive deficit associated with a central nervous system (CNS)disorder or condition in an animal, comprising treating the animal withan augmenting agent that enhances CREB pathway function in conjunctionwith cognitive training, wherein the augmenting agent is a compound orcomposition of the present invention. Exemplary compounds of the presentinventions, for example, have been shown to activate CREB in cell-basedassays.

In one aspect, the method comprises: (a) providing cognitive training toa subject in need of treatment of a cognitive deficit under conditionssufficient to produce an improvement in performance by said animal of acognitive function whose impairment is associated with said cognitivedeficit; (b) administering a compound or composition of the presentinvention to the animal in conjunction with said cognitive training;repeating steps (a) and (b) one or more times; and (d) reducing thenumber of training sessions sufficient to produce the improvement inperformance, relative to the same improvement in performance produced bycognitive training alone.

In another aspect, the method comprises: (a) providing cognitivetraining to a subject in need of treatment of a cognitive deficit underconditions sufficient to produce an improvement in performance by saidanimal of a cognitive function whose impairment is associated with saidcognitive deficit; (b) administering a compound or composition of thepresent invention to the animal in conjunction with said cognitivetraining; repeating steps (a) and (b) one or more times; and (d)producing a long-lasting improvement in performance of said functionrelative to the improvement in performance of said function produced bycognitive training alone.

In one aspect, a compound or composition of the present invention can beused as an augmenting agent in conjunction with any psychotherapeuticapproach intended to modulate cognitive function in the brain, therebyenhancing the efficacy of such therapy by reducing the number ofsessions necessary to attain benefits.

In another aspect, the cognitive deficit treated by these methods is orincludes memory impairment, and more particularly, a defect in long-termmemory. Long-term memory (LTM) generally comprises two main biologicalproperties. First, formation of long-term memory requires synthesis ofnew proteins. Second, it involves cAMP-responsive transcription and ismediated through the cAMP-response element binding protein (CREB) familytranscription factors. Compounds of the present invention can act asCREB-augmenting agents and are therefore useful in enhancing memoryformation in an animal, and more particularly, transcription-dependentmemory. Indeed, exemplary compounds of the present invention activateCREB in cell-based assays.

In some embodiments, the invention provides methods of treating a motordisorder, and more particularly, methods for improving a motor deficitassociated with a central nervous system (CNS) disorder or condition inan animal comprising treating the animal with an augmenting agent thatenhances CREB pathway function in conjunction with motor training.Methods are also provided herein for providing sustained improvement ina motor deficit associated with a central nervous system (CNS) disorderor condition in an animal in need of said treatment comprisingadministering to the animal a compound or composition of the presentinvention; and detecting said sustained improvement

In one aspect, the method comprises: (a) providing motor training to asubject in need of treatment of a motor deficit under conditionssufficient to produce an improvement in performance by said animal of amotor function whose impairment is associated with said cognitivedeficit; (b) administering a compound or composition of the presentinvention to the animal in conjunction with said motor training;repeating steps (a) and (b) one or more times; and (d) reducing thenumber of training sessions sufficient to produce the improvement inperformance, relative to the same improvement in performance produced bymotor training alone.

In another aspect, the method comprises: (a) providing motor training toa subject in need of treatment of a motor deficit under conditionssufficient to produce an improvement in performance by said animal of amotor function whose impairment is associated with said cognitivedeficit; (b) administering a compound or composition of the presentinvention to the animal in conjunction with said motor training;repeating steps (a) and (b) one or more times; and (d) producing along-lasting improvement in performance of said function relative to theimprovement in performance of said function produced by motor trainingalone.

In other embodiments, the invention provides methods for enhancing aspecific aspect of cognitive performance in an otherwise healthy animal(particularly in a human or other mammal or vertebrate) comprising (a)administering to the animal an augmenting agent of the presentinvention; and (b) training the animal under conditions sufficient toproduce an improvement in performance of a particular cognitive task bythe animal. In other embodiments, the present invention provides methodsof enhancing cognitive or motor performance, as well as methods forrepeated stimulation of neuronal activity or a pattern of neuronalactivity, such as that underlying a specific neuronal circuit(s).

Augmenting Agents

Augmenting agents, including the compounds and compositions herein, areable to enhance CREB pathway function. By enhancing CREB pathwayfunction in conjunction with training, such augmented training candecrease the number of training sessions required to improve performanceof a cognitive or motor function, relative to the improvement observedby training alone (e.g., U.S. 2007-0203154, U.S. 2011-0160248, U.S.2010-0317648, and U.S. Pat. No. 8,222,243).

The augmenting agent can be administered before, during or after one ormore of the training sessions. In a particular embodiment, theaugmenting agent is administered before and during each trainingsession. Treatment with an augmenting agent in connection with eachtraining session is also referred to as the “augmenting treatment”.

Training Protocols

Training protocols are generally employed in rehabilitating individualswho have some form and degree of cognitive or motor dysfunction. Forexample, training protocols are commonly employed in strokerehabilitation and in age-related memory loss rehabilitation. Becausemultiple training sessions are often required before an improvement orenhancement of a specific aspect of cognitive (or motor) performance(ability or function) is obtained in the individuals, training protocolsare often very costly and time-consuming. Augmented training methods aremore efficacious and therefore more cost-effective.

For example, human brain injury often results in motor and cognitiveimpairments. While advances in critical care medicine and patientmanagement have led to improvements in patient outcome followingtraumatic brain injury (TBI), there is currently no known treatment toprevent the neuronal cell death and dysfunction that follows TBI.Although multiple treatments have proven neuroprotective in pre-clinicalmodels of TBI, most have failed to show efficacy in humans.

Once a patient is stabilized following TBI, the standard of caredictates extensive motor or cognitive rehabilitation. During thisrehabilitation the patient often regains lost skills, finally resultingin improved functional outcome. It would be beneficial if pharmaceuticaltreatments could be developed to enhance motor or cognitiverehabilitation following TBI, and thus improve functional outcome.

Cognitive and motor training protocols and the underlying principles arewell known in the art (e.g., Allen et al., Parkinsons Dis. 2012, 1-15;Jaeggi et al., Proc. Natl. Acad. Sci. USA 2011, 108, 10081-10086; Chemet al., Psychon. Bull. Rev. 2010, 7, 193-199; Klingberg, Trends Cogn.Sci. 2010, 14, 317-324; Owen et al., Nature 2010, 465, 775-778; Tsao etal., J. Pain 2010, 11, 1120-1128; Lustig et al., Neuropsychol. Rev.2009, 19, 504-522; Park and Reuter-Lorenz, Ann. Rev. Psych. 2009, 60,173-196; Oujamaa et al., Ann. Phys. Rehabil. Med. 2009, 52, 269-293;Frazzitta et al., Movement Disorders 2009, 8, 1139-1143; Jaeggi et al.,Proc. Natl. Acad. Sci. USA 2008, 105, 6829-6833; Volpe et al.,Neurorehabil. Neural Repair 2008, 22, 305-310; Fischer et al., Top.Stroke Rehab. 2007, 14, 1-12; Jonsdottir et al., Neurorehabil. NeuralRepair 2007, 21, 191-194; Stewart et al., J. Neurol. Sci. 2006, 244,89-95; Krakauer, Curr. Opin. Neurol. 2006, 19, 84-90; Belleville et al.,Dement. Geriatr. Cogn. Disord. 2006, 22, 486-499; Klingberg et al., J.Am. Acad. Child. Adolesc. Psychiatry 2005, 44, 177-186; Dean et al.,Arch. Phys. Med. Rehabil. 2000, 81, 409-417; Whitall et al., Stroke2000, 31, 2390-2395; Hummelsheim and Eickhof, Scand. J. Rehabil. Med.1999, 31, 250-256; Merzenich et al., Science 1996, 271, 77-81; Merzenichet al., Cold Spring Harb. Symp. Quant. Biol. 1996, 61, 1-8; Rider andAbdulahad, Percept. Mot. Skills 1991, 73, 219-224; Wek and Husak,Percept. Mot. Skills, 1989, 68, 107-113;

Cognitive training protocols are directed to numerous cognitivedimensions, including memory, concentration and attention, perception,learning, planning, sequencing, and judgment. Motor training protocolscan be directed to numerous motor domains, such as the rehabilitation ofarm or leg function after a stroke or head injury. One or more protocols(or modules) underling a training program can be provided to a subject.

In some embodiments, the protocols can be used to treat, orrehabilitate, cognitive or motor impairments in afflicted subjects. Suchprotocols may be restorative or remedial, intended to reestablish priorskills and functions, or they may be focused on delaying or slowingcognitive or motor decline due to neurological disease. Other protocolsmay be compensatory, providing a means to adapt to a cognitive or motordeficit by enhancing function of related and uninvolved brain domains.In other embodiments, the protocols can be used to improve particularskills or cognitive or motor functions in otherwise healthy individuals.For example, a cognitive training program might include modules focusedon delaying or preventing cognitive decline that normally accompaniesaging; here the program is designed to maintain or improve cognitivehealth.

In general, a training protocol (or module) comprises a set of distinctexercises that can be process-specific or skill-based: Process-specifictraining focuses on improving a particular domain such as attention,memory, language, executive function, or motor function. Here the goalof training is to obtain a general improvement that transfers from thetrained activities to untrained activities associated with the samecognitive or motor function or domain. For example, an auditorycognitive training protocol can be used to treat a student with impairedauditory attention. At the end of training, the student should show ageneralized improvement in auditory attention, manifested by anincreased ability to attend to and concentrate on verbal informationpresented in class—and therefore to remember to write down and completehomework assignments. Similarly, a cognitive training protocol may bedirected to impaired executive function in an autistic subject,preventing the subject from carrying out instructions to complete anactivity, such as making a meal, cleaning one's room, or preparing forschool in the morning. Cognitive training allows the subject to focushis attention and concentration and as a result, complete the sequenceof tasks required for such activities.

Skill-based training is aimed at improving performance of a particularactivity or ability. Here the goal of training is to obtain a generalimprovement in the skill or ability. For example, a training protocolmay focus on learning a new language, performing a musical instrument,improving memory, or learning a fine motor skill. The differentexercises within such a protocol will focus on core componentsunderlying the skill Modules for increasing memory, for example, mayinclude tasks directed to the recognition and use of fact, and theacquisition and comprehension of explicit knowledge rules.

Some rehabilitation programs may rely on a single strategy (such ascomputer-assisted cognitive training) targeting either an isolatedcognitive function or multiple functions concurrently. For example, theCogState testing method comprises a customizable range of computerizedcognitive tasks able to measure baseline and change in cognitive domainsunderlying attention, memory, executive function, as well as languageand social-emotional cognition (e.g., Yoshida et al., PloS ON, 2011, 6,e20469; Frederickson et al., Neuroepidemiology 2010, 34, 65-75). Otherrehabilitation programs may use an integrated or interdisciplinaryapproach. Cognitive and motor training programs may involve computergames, handheld game devices, interactive exercises, and may employfeedback and adaptive models.

Neurorehabilitation and Neurorecovery

In other embodiments, the invention further relates to the use ofcompounds and compositions of the present invention in neurorecovery andneurorehabilitation—endogenous neurobiological processes that arecentral to recovery of cognitive and motor impairments of the nervoussystem (e.g., Harkema et al., “Locomotor training: as a treatment ofspinal cord injury and in the progression of neurologic rehabilitation”,Arch. Phys. Med. Rehabil. 2012, 93, 1588-1597; Muresanu et al., “Towardsa roadmap in brain protection and recovery”, J. Cell. Mol. Med. 2012,16, 2861-2871).

Neurorehabilitation or neurorecovery generally refers to a collectionprocess that focuses on aiding a person's recovery from a neurologicaldisorder, or helping that individual to live a more normal, active, andindependent life. For example, the quality of life of a person can begreatly affected by a brain or spinal cord injury, or a medicalcondition which affects the mobility, cognitive functions, or otherphysical or psychological processes that have been affected by changesin the nervous system. The goal of neurorehabilitation is to combatthose changes and improve quality of life by various therapies.

Conditions within the scope of the invention that are treated byneurorehabilitation and neurorecovery include: Stroke; traumatic braininjury (TB); Dementia; Alzheimer's disease; Parkinson's disease;Huntington's disease; Cerebral palsy; Post-polio syndrome;Guillain-Barre syndrome, and Multiple Sclerosis; and other developmentalsyndromes, genetic conditions, and progressive CNS diseases affectingcognitive function, such as autism spectrum disorders, fetal alcoholspectrum disorders (FASD), Rubinstein-Taybi syndrome, Down syndrome, andother forms of mental retardation.

By focusing on all aspects of a person's well-being, neurorehabilitationor neurorecovery offers a series of therapies from the psychological tooccupational, teaching or re-training patients on mobility skills,communication processes, and other aspects of that person's dailyroutine. Neurorehabilitation or neurorecovery also provides focuses onnutrition, psychological, and creative parts of a person's recovery.

In one embodiment, the present invention provides a method of augmentingneurorehabilitation or neurorecovery from a cognitive impairment,comprising (a) providing cognitive training to a subject in need oftreatment of a cognitive deficit under conditions sufficient to producean improvement in performance by said animal of a cognitive functionwhose impairment is associated with said cognitive deficit; (b)administering a compound or composition of the present invention to theanimal in conjunction with said cognitive training; repeating steps (a)and (b) one or more times; and (d) producing a long-lasting improvementin performance of said function relative to the improvement inperformance of said function produced by cognitive training alone.

In another embodiment, the present invention provides a method ofaugmenting neurorehabilitation or neurorecovery from a motor impairment,comprising: (a) providing motor training to a subject in need oftreatment of a motor deficit under conditions sufficient to produce animprovement in performance by said animal of a motor function whoseimpairment is associated with said cognitive deficit; (b) administeringa compound or composition of the present invention to the animal inconjunction with said motor training; repeating steps (a) and (b) one ormore times; and (d) reducing the number of training sessions sufficientto produce the improvement in performance, relative to the sameimprovement in performance produced by motor training alone.

Non-Human Animal Training Protocols

Aside from applications for humans, compounds and compositions of thepresent invention have additional uses for non-human animals, namely inenhancing (augmenting) the efficiency of training protocols directed tonumerous cognitive and motor functions.

Conditions, under which non-human animals would benefit, includeenhanced (augmented) training procedures for specific purposes, (e.g.hunting dogs, guide dogs, police dogs etc, or animals used in movieindustry).

Enhanced training protocols can also benefit animals that have beenexposed to stressful or traumatic conditions and are in need of trainingto treat the resulting cognitive impairments. Such a need may arise, forexample, after such an animal has been captured or transported,subjected to new housing conditions (as in a change of domicile orowner), or has developed analogous disorders and is distressed oraggressive, or displays stereotypic behavior, obsessive-compulsivebehavior, or anxiety. Animals which are subject to stress would alsoinclude animals used in racing (eg. dogs, horses, camels) or othersports, performing animals (such as circus animals and those appearingon stage, television or in the movies) and horses that perform dressageand other highly disciplined routines.

Compounds of the present invention can also enhance the efficiency ofrehabilative protocols following physical injury to a non-human animal,such as limb amputation. For example, administering an augmenting agentof the present invention in conjunction with a training protocol canincrease the efficiency of a rehabilitative program by decreasing thenumber of training sessions necessary to achieve an improvement in motorfunction.

In particular embodiments, compounds and compositions of the presentinvention are used in methods of training service animals. By combiningaugmenting agents of the present invention with training protocols, theefficiency of training non-human animals for service in both the publicand private sectors will be enhanced. Service animals are typicallydogs. However, other non-human animals can also be trained to performservices, such as assisting blind or disabled people. For example,miniature horses can be trained to guide the blind, to pull wheelchairs,or to provide support for Parkinson's patients. As another example,capuchin monkeys can be trained to assist disabled perform manual tasks,such as grasping items, operating knobs and switches, turning the pagesof a book.

In specific embodiments, augmented training with compounds andcompositions of the present invention can be used to reduce the numberof training sessions necessary to teach an animal skills that are usefulin public service, such as in law enforcement. In dogs, for example,such skills include, but are not limited to, the following: (i) publicorder maintenance, e.g., chasing, holding, or detaining suspects; (ii)search and rescue, e.g., locating suspects, missing persons, or objects;and (iii) contraband detection, e.g., detecting illicit substances suchas drugs, narcotics, explosives, weapons, and even human remains. Suchmethods can therefore be applied to police dogs, bomb-sniffing dogs,drug-sniffing dogs, search and rescue dogs, etc.

In other embodiments, augmented training (with compounds andcompositions of the present invention) can be used to reduce the numberof training sessions required to teach animals skills that are useful inthe private sector, such as security and medical care. In dogs, forexample, such skills can include, but are not limited to, the following:(i) private security, e.g., guarding property or protecting anindividual; (ii) handicap assistance, e.g., providing eyes for thevisually impaired, ears for the hearing-impaired, arms and legs for thephysically-disabled; (iii) health care, e.g., detecting cancer oraltering a caregiver to seizures in a subject; (iv) psychiatricassistance, e.g., calming a phobic person under stress-triggeringconditions, or alerting an autistic person to distracting repetitivemovements such as hand flapping; and (v) pest control, e.g., identifyingsource of infestations by bedbugs or termites.

In some embodiments, the training protocol can be directed to a singleskill or task, such as the detection of a single drug. In otherembodiments, the training protocol can be directed to a complex set ofskills, such as those underlying search and rescue. For a complex set ofskills, training will therefore comprise more than one task.

In another aspect, when training is carried out with a wide enough scopeof tasks, a generalized “rehabilitation” effect is expected, resultingin generalized improved function of one or more cognitive domains. Thisresults in improved performance of the animal of related tasks(involving the same cognitive domains) that are not specifically part ofthe training protocol.

Accordingly, the present invention provides a method of reducing thetime necessary to teach an animal one or more skills, wherein saidreducing comprising: a) administering an augmenting agent of the presentinvention to the animal; b) providing a training protocol to said dogunder conditions to improve performance of one or more tasks, whereinsaid training protocol comprises multiple training sessions; and c)decreasing the number of training sessions required to improveperformance of said one or more tasks relative to the number of saidtraining sessions required to produce said improvement in performance bythe training protocol alone.

The training protocol can be provided to the animal under conditions toimprove performance of a single task; a complex set of tasks; or a widescope of tasks, resulting in generalized improved function of one ormore cognitive domains. The tasks can relate to a skill involved inpublic service, such as public order maintenance, search and rescue, andcontraband detection. The tasks can also relate to a skill involved inprivate service, such as private security, handicap assistance, healthcare, psychiatric assistance, and pest control.

Peripheral Disorders

PDE4 enzymes are located in a number of peripheral tissues. For example,one or several PDE4D isoforms are expressed throughout most tissuestested, including cortex, hippocampus, cerebellum, heart, liver, kidney,lung and testis (Richter et al., Biochem. J., 2005, 388, 803-811). Thelocalization and regulation of PDE4D isoforms is thought to allow fortight and local regulation of cAMP levels, possibly limiting signalpropagation in specific subcellular compartments.

Thus, in one embodiment, the invention provides a method of treating aperipheral disorder associated with PDE4, by administering to an animalin need thereof a therapeutically effective amount of a compound orpharmaceutical composition described herein.

The peripheral disorder may include, but is not limited to, suchPDE4-associated disorders as inflammatory bowel disease (Banner andTrevethick, 2004, Trends Pharmacol. Sci. 25, 430-436); rheumatoidarthritis (Kobayashi et al., 2007, Mediators Inflamm. 2007, 58901);chronic obstructive pulmonary disease (COPD), asthma, allergic rhinitis,pulmonary artery hypertension (DeFranceschi et al., 2008, FASEB J., 22,1849-1860); renal diseases (Conti et al., 2003, J. Biol. Chem., 278,5493); allergic skin diseases and psoriasis (Baumer et al., 2007,Inflamm. Allergy Drug Targets, 6, 17-26).

EXAMPLES

The present disclosure will be further illustrated by the followingnon-limiting Examples. These Examples are understood to be exemplaryonly, and they are not to be construed as limiting the scope of theinvention herein, and as defined by the appended claims.

PREPARATIVE EXAMPLES

Exemplary compounds useful in methods of the invention will now bedescribed by reference to the illustrative synthetic schemes for theirgeneral preparation below and the specific examples to follow.

Synthetic Schemes

One skilled in the art will recognize that, to obtain the variouscompounds herein, starting materials may be suitably selected so thatthe ultimately desired substituents will be carried through the reactionscheme with or without protection as appropriate to yield the desiredproduct. Alternatively, it may be necessary or desirable to employ, inthe place of the ultimately desired substituent, a suitable group thatmay be carried through the reaction scheme and replaced as appropriatewith the desired substituent. Unless otherwise specified, the variablesare as defined above in reference to Formula (I). Reactions may beperformed between −78° C. and the reflux temperature of the solvent.Reactions may be heated employing conventional heating or microwaveheating. Reactions may also be conducted in sealed pressure vesselsabove the normal reflux temperature of the solvent.

According to Scheme A, commercially available or syntheticallyaccessible 3-bromo-5-methylpyridin-2-ol (II) is difluoromethylated with2,2-difluoro-2-(fluorosulfonyl)acetic acid or the silyl ester of2-fluorosulfonyldifluoroacetate, preferably2,2-difluoro-2-(fluorosulfonyl)acetic acid, in an aprotic solvent, suchas ACN, a base, such as Na₂CO₃, NaH, and the like, preferably Na₂CO₃, attemperatures ranging from room temperature to the reflux temperature ofthe solvent, preferably room temperature, to afford a compound offormula (VI) where Z is CH and R₄ is CHF₂ (Chen et al., J. FlourineChem., 1989, 44, 433-440).

According to Scheme A, compounds of formula (VI), where Z is CH, R⁴ is—C₁₋₃alkyl or —C₁₋₃haloalkyl, are prepared from commercially availableor synthetically accessible 3-bromo-2-chloro-5-methylpyridine (III).Reaction of 3-bromo-2-chloro-5-methylpyridine (III), with an alkoxide,such as sodium ethoxide, sodium methoxide and the like, in a suitablesolvent, such as the alcohol used to generate the alkoxide, attemperatures ranging from room temperature to the reflux temperature ofthe solvent, for a period of 4 to 48 h provides bromopyridyl ethers offormula (VI). Alternatively, compounds of formula (VI), where R⁴ is—C₁₋₃alkyl or —C₁₋₃haloalkyl, may be prepared by reaction of3-bromo-2-chloro-5-methylpyridine with a suitably substituted primary orsecondary alcohol, in the presence of a base such as NaH, in a solvent,such as DMA, 1,4-dioxane, THF, and the like, at temperatures rangingfrom room temperature to the reflux temperature of the solvent.

According to Scheme A, commercially available or syntheticallyaccessible 5-methylpyrazin-2-amine (IV), where 1Z¹ is H, U is CH₃, and Zis N), is brominated under conditions known to one skilled in the art,for example, by reaction with a suitable halogenating agent such as NBS,Br₂, and the like, in an appropriate solvent such as DCM, 1,4-dioxane,THF, CHCl₃, preferably DCM, at temperatures ranging from 0° C. to roomtemperature, for a period of 8 to 16 h to afford3-bromo-5-methylpyrazin-2-amine. Subsequent reaction of3-bromo-5-methylpyrazin-2-amine (V) with an oxidizing agent, such as,but not limited to, tert-butyl nitrite, in the presence of an anhydrousacid source, for example, HCl in 1,4-dioxane, in an alcoholic solventsuch as MeOH, EtOH, and the like, at temperatures ranging from 0° C. to60° C., for a period of 8 to 16 h affords compounds of formula (VI),where Z is N, U is —CH₃, and R₄ is —C₁₋₃alkyl. According to Scheme A,commercially available or synthetically accessible6-amino-2-methylnicotinonitrile (IV), where 1Z¹ is —CH₃, U is —CN, and Zis CH is prepared in two steps (bromination and diazotizationalcoholaddition) by the methods previously described to provide compounds offormula (VI) where 1Z¹ is —CH₃, U is —CN, and Z is CH.

According to Scheme B,2-(difluoromethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)pyridine(IX) is obtained in 2 steps from commercially available4-bromo-2-hydroxypyridine (VII). Alkylation of 4-bromo-2-hydroxypyridine(VII), with 2-chloro-2,2-difluoroacetate in a solvent such as ACN, THF,1,4-dioxane, or a mixture thereof, at temperatures ranging from roomtemperature to the reflux temperature of the solvent, for a period of6-12 h (also described in WO2010056195, May 20, 2010) provides4-bromo-2-(difluoromethoxy)pyridine (VIII). Boronate esters are preparedusing methods known to one skilled in the art, for example,2-difluoromethoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine(IX) is prepared from 4-bromo-2-(difluoromethoxy)pyridine (VIII) byreaction with KOAc, K₃PO₄, and the like, a catalyst such as Pd(dppf)Cl₂,Pd(PPh₃)₄, and the like, bis(pinacolato)diboron, and the like, in asolvent such as 1,4-dioxane, 1-2-dimethoxyethane, DMF, DMSO, and thelike, at temperatures ranging from 60 to 150° C., for a period of 6-24h.

As shown in Scheme C, compounds of formula (VI), where U is —CH₃, —CN or—NH₂, Z is CH or N; R¹ is H or —CH₃, and R⁴ is —C₁₋₃alkyl or—C₁₋₃haloalkyl; under Suzuki reaction conditions known to one skilled inthe art, are reacted with commercially available or syntheticallyaccessible aromatic or heteroaromatic boronic acids or esters, orsynthetically accessible heteroaromatic boronic esters, such as compound(IX), in a solvent such as ACN, toluene, EtOH, H₂O, or a mixturethereof, in the presence of a base such as, NaHCO₃, Na₂CO₃, K₂CO₃,Cs₂CO₃, and the like, and a palladium catalyst such as, Pd(dppf)₂,Pd(Ph₃)₄, and the like, using conventional or microwave heating, attemperatures ranging from 80 to 120° C. provides compounds of formula(X). Compounds of formula (X) where R³ is aryl or heteroaryl optionallysubstituted with —OH, under standard alkylating conditions known to oneskilled in the art, are treated with commercially available orsynthetically accessible alkyl groups with appropriate leaving groups,such as halides, for example —Cl, —Br or —I, or sulfonates, such asmethanesulfonyl, p-toluenesulfonyl and the like, in the presence of abase, such as but not limited to, NaH, K₂CO₃, Cs₂CO₃, and the like, in asolvent such as DMF, DMSO, 1,4-dioxane, and the like, at temperaturesranging from 60° C. to the reflux temperature of the solvent for aperiod of 8 to 24 h, to provide aryl or heteroaryl O-alkyl compounds offormula (X).

Halogenation of compounds of formula (X), where U is —CH₃, Z is CH or N;R¹ is H or —CH₃, R₃ is aryl or heteroaryl, and R⁴ is —C₁₋₃alkyl or—C₁₋₃haloalkyl, under standard halogenation conditions, for example,NBS, a radical initiator such as AIBN or benzoyl peroxide, in a solventsuch as CCl₄, at temperatures ranging from 60° C. to the refluxtemperature of the solvent, for a period of 4 to 24 h, providescompounds of formula (XI), where HAL is —Br.

Nitrile compounds of formula (X), where U is —CN, Z is CH; R¹ is —CH₃,R₃ is aryl or heteroaryl, and R⁴ is —CH₃, are reduced to thecorresponding aldehyde with a reducing agent such as diisobutylaluminumhydride, and the like, in a solvent such as DCM, THF, toluene, and thelike, at low temperature, preferably −78° C., for a period of 1 to 3 h.Subsequent reduction of the aldehyde moiety to the correspondingalcohol, is accomplished with a reducing agent, such as sodium orlithium borohydride, and the like, in a solvent such as MeOH, THF, andthe like, at temperatures ranging from 0° C. to room temperature.Activation of the alcohol using methanesulfonyl chloride, in a suitablesolvent, such as DCM, in the presence of an alkylamine base, such asHünig's base, TEA, and the like, provides compounds of formula (XI),where U is —CN, Z is CH; R¹ is —CH₃, R⁴ is —CH₃ and HAL is —Cl.

According to Scheme C, 5-bromo-6-methoxypyridin-3-amine, where U is—NH₂, Z is CH; R¹ is H, R⁴ is —CH₃, is reacted under standard Suzukireaction conditions as previously described, to provide compounds offormula (X), where U is —NH₂, Z is CH; R¹ is H, R³ is aryl orheteroaryl, and R⁴ is —CH₃. Alternately, compounds of formula (X), maybe prepared from commercially available or synthetically accessiblesuitably substituted pyridine amines, such as,5-bromo-6-ethoxypyridin-3-amine, as outlined in the procedures describedabove, where U is —NH₂, Z is CH; R¹ is H, R³ is aryl or heteroaryl, andR⁴ is —C₁₋₃alkyl.

According to Scheme D, compounds of formula (XII), under Sandmeyerconditions known to one skilled in the art, are reacted with anoxidizing agent, such as, but not limited to, tert-butyl nitrite, in thepresence of a halogenating agent, for example copper(II)bromide, in anappropriate solvent, such as ACN and the like, at a suitabletemperature, preferably 60° C., affords compounds of formula (XIII)Lithiation of compounds of formula (XIII) with a suitable metallo-base,such as n-BuLi or the like, in a non-protic solvent, such as THF, Et₂Oor the like, at a low temperature, preferably −78° C., for a period of30-60 minutes, prior to addition of an appropriate aryl orheteroarylcarbonyl compound, followed by additional stirring attemperatures ranging from −78° C. to ambient temperature, providescompounds of Formula (I), where Y is CHOH, Z is CH, R² and R³ aremonocyclic aromatic or heteroaromatic rings, and R⁴ is —CH₃.

Fluoro compounds of Formula (I), where Y is —C(R^(a))₂—, and R^(a) is —Hor —F; are prepared by the reaction of alcohols of Formula (I), where Yis CH(OH), employing fluorinating conditions such, but not limited to,reaction with Deoxo-Fluor®, XtalFluor® and the like, in a solvent suchas DCM and the like, at room temperature, for a period of 1 to 24 h.

Compounds of Formula (I), where Y is —C(R^(a))₂—, and R^(a) is —H areprepared by treating the alcohols of Formula (I), where Y is CH(OH),with a reducing agent, such as but not limited to triethylsilane in thepresence of an acid source, such as trifluoroacetic acid, triflic acidand the like, in a solvent such as DCM and the like, at roomtemperature, for a period up to 24 h.

Amine compounds of Formula (I), where Y is —CHNH₂—, —CHNH(CH₃)—, or—CHN(CH₃)₂—, are prepared in two steps by the reaction of alcohols ofFormula (I), where Y is —CH(OH), with a chlorinating agent, such asthionyl chloride, oxalyl chloride and the like, with or without acatalytic amount of DMF, in a solvent such as DCM, and the like, attemperatures ranging from 0° C. to room temperature to provide thechloro intermediate which is then reacted with the appropriate amine,such as, but not limited to ammonia, methylamine and the like, with orwithout a catalytic amount of sodium iodide, in solvent such as ACN, ata temperature ranging from room temperature to 80° C.

As described in Scheme E, compounds of Formula (I) can be obtained fromcompounds of formula (IX) thru reactions such as, but not limited to,Suzuki or Negishi coupling reactions, and substitution reactions withnitrogen heteroaryls, Compounds of formula (IX) are reacted, employingstandard Suzuki coupling conditions, known to those skilled in the artand previously described herein, with commercially available aromatic orheteroaromatic boronic acids or esters, or synthetically accessibleheteroaromatic boronic esters, such as compound (1V), to give compoundsof Formula (I).

Compounds of formula (IX) are reacted, employing standard Negishicoupling conditions, known to those skilled in the art. An example ofNegishi reaction conditions are: coupling commercially available halogencontaining aromatic or heteroaromatic intermediates, with a preformedzincate obtained from reacting compounds of formula (IX) with zinc,pretreated with activators such as trimethylsilyl chloride and1,2-dibromoethane, in an appropriate solvent, such as THF, 1,4-dioxane,and the like, at a temperature ranging from room temperature to refluxtemperature, preferably reflux temperature, for a period of 12 to 24 h.Combining the zincate intermediate with commercially available halogencontaining aromatic or heteroaromatic compounds in the presence of apalladium catalyst, such as Pd(PPh₃)₄ and the like, in a suitablesolvent, such as THF, 1,4-dioxane, and the like, at temperatures rangingfrom 50° C. to the reflux temperature of the solvent, for a period of 12to 48 h, affords compounds of Formula (I), where R² is a six memberedheteroaryl ring containing one to two nitrogen members.

Compounds of formula (IX) when combined with the appropriate heterocycle(HET) with an acidic proton, such as but not limited to,1H-1,2,4-triazole or imidazole, in an aprotic solvent, for example DMF,acetone, ACN, and the like, with a suitable base, such as Cs₂CO₃, K₂CO₃,and the like, at temperatures ranging from room temperature to 60° C.,for period of 2 to 24 h, provides compounds of Formula (I), where R² isa five membered heteroaryl ring containing two to three nitrogenmembers.

Compounds of Formula (I), where Y is —CH₂, and R² is an optionallysubstituted 1,2,3-triazole are obtained using “Click Chemistry” (forexample, copper-catalyzed azide-alkyne cycloaddition) under conditionsknown to one skilled in the art, for example, by treating compounds offormula (IX) with sodium azide in a suitable solvent, such as DMF,acetone, DMSO, and the like, and base such as K₂CO₃, and the like, attemperatures ranging from room temperature to 100° C., affords the azidointermediate which is then combined with a commercially available orsynthetically accessible alkyne, such as but not limited toethynyltrimethylsilane, and the like, in a solvent such as DMSO,1,4-dioxane, THF, ACN, t-butanol, and water or a mixture thereof, in thepresence of a catalyst, for example copper(II)iodide, copper(II)bromide,copper(I)sulfate, and the like, and base, such as Hünig's base, and thelike, at temperatures ranging from room temperature to 100° C., for aperiod of 2 to 12 h, provides compounds of Formula (I), where R² is anoptionally substituted 1,2,3-triazole.

Compounds of Formula (I), where R² is substituted with an amide(—CONH₂), are prepared from the corresponding nitriles (—CN) or esters(—CO₂C₁₋₃alkyl) using methods known to those skilled in the art. Forexample, amides of Formula (I) are obtained by reaction of nitrilecompounds of Formula (I) with a base, such as NaOH or KOH, preferablyNaOH, and a peroxide, such as hydrogen peroxide, in a solvent such asMeOH, and the like, at a temperatures ranging from 0 to 50° C., for aperiod of 8 to 24 h. Optionally, carboxylic acid compounds of Formula(I) are obtained when nitrile compounds of Formula (I) are treated asdescribed above at a temperature of 50° C., for a period of 2 to 4 h.Ester compounds of Formula (I) are converted to amides of Formula (I) bytreating with an appropriate amine, such as ammonia, methylamine or thelike, in a solvent, such as MeOH, 1,4-dioxane, and the like, attemperatures ranging from room temperature to the reflux temperature ofthe solvent.

Compounds of Formula (I), where R² is substituted with a primary(—CH₂OH) or tertiary (—C(CH₃)₂OH) alcohol were prepared from thecorresponding aldehyde or ester compounds of Formula (I), using methodsknown to those skilled in the art. Reduction of aldehyde compounds ofFormula (I) with a reducing agent, such as NaBH₄ or sodiumcyanoborohydride, and the like, in a solvent such as MeOH, THF, DMF andthe like, at temperatures ranging from 0° C. to room temperature, for aperiod of 0.2 to 2 h, affords primary alcohol compounds of Formula (I),where R² is substituted with —CH₂OH. Compounds of Formula (I), where R²is substituted with an ester moiety, are reduced, with a reducing agent,such as lithium borohydride, lithium aluminum hydride, and the like, ina solvent such as MeOH, THF, Et₂O and the like, at temperatures rangingfrom 0° C. to room temperature, for a period of 2 to 24 h, affordsprimary alcohol compounds of Formula (I), where R² is substituted with—CH₂OH.

Compounds of Formula (I), where R² is substituted with —CH₂OH or —CHO,are fluorinated, employing fluorinating conditions such as, but notlimited to, reaction with Deoxo-Fluor®, XtalFluor® and the like, in asolvent such as DCM and the like, room temperature, for a period of 2 to24 h, to provide fluoroalkyl compounds of Formula (I), where R² issubstituted with —CH₂F or —CHF₂.

Compounds of Formula (I), where R² is substituted with an ester moiety,are reacted under Grignard conditions known to one skilled in the art,with a Grignard reagent such as, but not limited to, methylmagnesiumbromide, in a solvent such as THF, Et₂O, and the like, at temperaturesranging from 0° C. to room temperature, for a period of 0.3 to 2 h, toprovide compounds of Formula (I), where R² is substituted with atertiary alcohol (—C(CH₃)₂OH).

Compounds of Formula (I), where R² is substituted with —CN, are reducedwith a reducing agent, such as diisobutylaluminum hydride and the like,in a solvent such as Et₂O, THF, and the like, at low temperatures,preferably −78° C., for a period of 1 to 4 h, to provide primary aminecompounds of Formula (I), where R² is substituted with primary amine(—CH₂NH₂).

Compounds of Formula (I), where R² is substituted with an ester moiety,are reacted under standard hydrolysis conditions known to one skilled inthe art, with a base such as, but not limited to, KOH, LiOH, NaOH andthe like, in a solvent such as THF, 1,4-dioxane, MeOH, H₂O or a mixturethereof, at temperatures ranging from room temperature to the refluxtemperature of the solvent, for a period of 1 to 4 h, to providecompounds of Formula (I), where R² is substituted with carboxylic acid(—CO₂H).

Compounds of Formula (I), where R² is an optionally substitutedpyrimidine with —Cl are reacted with an amine, such asN1,N1-dimethylethane-1,2-diamine, and the like, in a solvent such asACN, a base such as N-ethyl-N-isopropylpropan-2-amine, and the like, attemperature ranging from 80 to 180° C., using conventional or microwaveheating conditions, for a period of 1 to 4 h, to provide aminesubstituted compounds of Formula (I), where R² is substituted with(—NHCH₂CH₂N(CH₃)₂).

Compounds of Formula (I), where R² is substituted with —NO₂, are reducedwith a reducing agent, such as, but not limited to zinc or iron, in asolvent such as acetic acid, water, or a mixture thereof, attemperatures ranging from room temperature to 50° C., for a period of 1to 4 h, to provide primary amine compounds of Formula (I), where R² issubstituted with primary amine (—NH₂).

Compounds of Formula (I), where R² is substituted with (—NHR^(b)) or(—N(R^(b))₂) are prepared from the corresponding amine compounds ofFormula (I), employing methods known to one skilled in the art, such asbut not limited to reductive amination reactions. For example, compoundsof Formula (I) where R² is substituted with (—NH₂), are reacted with anappropriate carbonyl intermediate, such as but not limited to,formaldehyde and the like, in a solvent such as THF, DCM, MeOH and thelike, with a reducing agent, such as sodium triacetoxyborohydride,sodium cyanoborohydride and the like, at temperatures ranging from 0 to50° C., for a period of 1 to 4 h, provides alkyl amine compounds ofFormula (I), where R^(b) is —CH₃.

Compounds of Formula (I), where R² is substituted with (—NHCOCH₃) areprepared from the corresponding amine compounds of Formula (I),employing methods known to one skilled in the art, such as but notlimited to, treatment with an acyl chloride or anhydride. For example,compounds of Formula (I) where R² is substituted with (—NH₂), aretreated with an appropriately activated acylating agent, such as but notlimited to, acetyl chloride, acetic anhydride and the like, in a solventsuch as, DCM, DMF and the like, with a base, such as TEA, Hünig's base,and the like, at temperatures ranging from 0° C. to room temperature,for a period of up to 24 h, provides acyl substituted amine compounds ofFormula (I), where R² is (—NHCOCH₃)

Compounds of Formula (I), where R² is substituted with (—NHCONH₂) areprepared from the corresponding amine compounds of Formula (I),employing methods known to one skilled in the art, such as but notlimited to, treatment with potassium cyanate and the like, in a solventsuch as, acetic acid and water or a mixture thereof, at temperaturesranging from room temperature to 60° C., for 0.2 to 4 h, to provide ureasubstituted compounds of Formula (I), where R² is (—NHCONH₂).Optionally, compounds of Formula (I), where R² is substituted with(—NHCONH-oxetane) are prepared from the corresponding carboxylic acidcompounds of Formula (I), using the Curtuis rearrangement employingmethods known to one skilled in the art. For example, compounds ofFormula (I) where R² is substituted with (—CO₂H), are treated with, butnot limited to, diphenylphosphoryl azide and the like, in the presenceof a base, such as TEA, Hünig's base, and the like, in an appropriatesolvent such as, toluene, 1,-4-dioxane, and the like, at the refluxtemperature of the solvent, for a period of up to 1 h. The intermediateacyl azide is then reacted with an appropriate amine, in the presence ofa base, such as TEA, Hünig's base, and the like, to afford the compoundsof Formula (I) where R² is substituted with (—NHCONH-oxetane)

Compounds of Formula (I), where R² is substituted with —NO₂, are reactedwith a commercially available or synthetically accessiblemetallo-alkoxide, for example, sodium methoxide, sodium ethoxide and thelike, in a solvent such as, but not limited to, MeOH, EtOH, 1,4-dioxaneand the like, at temperatures ranging from room temperature to thereflux temperature of the solvent, for a period of 24 h, to providecompounds of Formula (I) where R² is substituted with (—OC₁₋₃alkyl).

Compounds of Formula (I), wherein R² is 1,2,3-triazole optionallysubstituted with —H, are synthesized from the corresponding4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl) compounds of Formula (I), byreacting with a desilylating agent, such as but not limited to,tetrabutylammonium fluoride, in a solvent such as THF, DMF, and thelike, at temperatures ranging from room temperature to 50° C., for aperiod of 8 to 24 h.

Compounds of Formula (I), where R² is substituted with —CHO, areprepared from the corresponding alcohols or esters, previously describedusing methods known to those skilled in the art. For example, treatingan alcohol of Formula (I) with an oxidizing agent, such as but notlimited to Dess-Martin® reagent, in an appropriate solvent, such as DCMor THF and the like, at room temperature for 3 to 8 h give the desiredaldehyde. The desired aldehydes of Formula (I) are also obtained bytreating the corresponding ester of Formula (I) with a reducing agent,such as diisobutylaluminum hydride, in an appropriate solvent, such asTHF, Et₂O and the like, at low temperature, preferably −78° C., for 1 to4 h.

Removal of the tert-butylcarbamate (BOC) in compounds of Formula (I)where R² is optionally substituted with (—NH—BOC) or (—HET-N—BOC) isaccomplished by using methods known to one skilled in the art, such as,HCl, TFA, or p-toluenesulfonic acid, in a solvent such as CH₃OH,dioxane, or CH₂Cl₂. In a preferred embodiment, a compound of formula istreated with TFA in DCM or HCl to afford a compound of Formula (I) whereR² is optionally substituted with (—NH₂) or (—HET-NH₂)

According to Scheme F, compounds of formula (VI) where U is —CH₃; R¹ isH, R⁴ is —C₁₋₃alkyl or —C₁₋₃haloalkyl, are halogenated according tomethods previously described to provide the corresponding alkylbromidecompounds. Subsequent reaction with HET, where HET is a five memberedheteroaryl ring selected from the group consisting of 1H-1,2,4-triazoleor imidazole, according to methods previously described, providescompounds of formula (XII) where R² is 1H-1,2,4-triazole or imidazole.

Compounds of formula (XII) are reacted, employing standard Suzukicoupling conditions, known to those skilled in the art and previouslydescribed herein, with commercially available aromatic or heteroaromaticboronic acids or esters, or synthetically accessible heteroaromaticboronic esters, such as compound (1V), to give compounds of Formula (I).

Optionally, compounds of Formula (I), where R³ is substituted withpyrazole are prepared from the corresponding compounds of formula (XII),employing methods known to one skilled in the art, such as but notlimited to, Buchwald coupling conditions. For example, compounds offormula (XII) are reacted with the appropriate heterocycle (HET) with anacidic proton, such as but not limited to, pyrazole, in a solvent, suchas toluene, 1,4-dioxane, and the like, with a suitable base, such assodium tert-butoxide, sodium methoxide, a palladium catalyst such as butnot limited to, tris(dibenzylideneacetone)dipalladium(0),palladium(II)acetate and the like, and a phosphine ligand, such as(2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl,tri(tert-butyl)phosphine and the like, at temperatures ranging from roomtemperature to the reflux temperature of the solvent, for period of 4 to48 h, provides compounds of Formula (I), where insert R³ is anoptionally substituted pyrazole.

Compounds of Formula (I) may be converted to their corresponding saltsusing methods known to those skilled in the art. For example, compoundsof Formula (I) may be treated with TFA, HCl, maleic acid, or citric acidin a solvent such as Et₂O, DCM, THF, or MeOH to provide thecorresponding salt forms.

Compounds prepared according to the schemes described above may beobtained as single enantiomers, diastereomers, or regioisomers, byenantio-, diastereo-, or regiospecific synthesis, or by resolution.Where compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.Compounds prepared according to the schemes above may alternately beobtained as racemic (1:1) or non-racemic (not 1:1) mixtures of mixturesas diastereomers or regioisomers. Where racemic and non-racemic mixturesof enantiomers are obtained, single enantiomers may be isolated usingconventional separation methods known to one skilled in the art, such aschiral chromatography, recrystallization, diastereomeric salt formation,derivatization into diastereomeric adducts, biotransformation, orenzymatic transformation. Where regioisomeric or diastereomeric mixturesare obtained, single isomers may be separated using conventional methodssuch as chromatography or crystallization.

The following examples are provided to further illustrate the inventionand various preferred embodiments.

EXAMPLES Chemistry

In obtaining the compounds described in the examples below, and thecorresponding analytical data, the following experimental and analyticalprotocols were followed unless otherwise indicated.

Unless otherwise stated, reaction mixtures were magnetically stirred atroom temperature (rt) under nitrogen atmosphere. Where solutions were“dried”, they were generally dried over a drying agent such as Na₂SO₄ orMgSO₄. Where mixtures, solutions, and extracts were “concentrated”, theywere typically concentrated on a rotary evaporator under reducedpressure.

Reactions under microwave irradiation conditions were carried out in aCEM Discover-SP with Activent microwave reaction apparatus, model number909150, or Biotage Initiator, model number 355302.

Normal-phase flash column chromatography (FCC) was performed on silicagel (SiO₂) using packed or prepackaged cartridges, eluting with theindicated solvents.

LCMS were obtained on a Waters 2695 Separations Unit, 2487 DualAbsorbance Detector, Micromass ZQ fitted with ESI Probe, or a WatersAcquity™ Ultra performance LC (UPLC) with PDA eλ and SQ detectors.

Nuclear magnetic resonance (NMR) spectra were obtained in a Varian 400MHz or Bruker 400 MHz NMR. Samples were analyzed in either deuteratedchloroform (CDCl₃), methanol-d₄ (CD₃OD), or dimethyl sulfoxide-d₆(DMSO-d₆). For CDCl₃ samples, tetramethylsilane (TMS) was used as aninternal standard with the TMS resonance set to a chemical shift of 0.00ppm for ¹H NMR spectra. For CD₃OD the residual central resonance peak at3.31 for ¹H was used for chemical shift assignment and for DMSO-d₆ theresidual central resonance peak at 2.50 ppm for ¹H was used for chemicalshift assignment. The format of the ¹H NMR data below is: chemical shiftin ppm downfield the tetramethylsilane reference (multiplicity, couplingconstant J in Hz, integration).

Chemical names were generated using ChemDraw Ultra 12.0 (CambridgeSoftCorp., Cambridge, Mass.) or ChemAxon.

Intermediate 1.5-(Bromomethyl)-3-(3-(difluoromethoxy)phenyl)-2-ethoxypyrazine

Step 1. 3-Bromo-5-methylpyrazin-2-amine. To a cooled, 0° C., solution of5-methylpyrazin-2-amine (5.00 g, 0.05 mol) in DCM (230 mL) was added1-bromopyrrolidine-2,5-dione (8.97 g, 0.05 mol) all at once. Thereaction mixture was allowed to warm to room temperature and stirred for12 h. The reaction was quenched with 1 N sodium thiosulfate (50 mL), thelayers were separated and the organic phase was extracted with water(2×50 mL). The combined organic layers were dried (Na₂SO₄), and thesolvent was removed under reduced pressure. Purification (FCC, SiO₂,0-50%, EtOAc/hexanes) afforded the title compound as a yellow solid(8.61 g, 65%). [M+H]=188.9190.11

Step 2. 3-Bromo-2-ethoxy-5-methylpyrazine. To a solution of3-bromo-5-methylpyrazin-2-amine (4.00 g, 21.27 mmol) in EtOH (42 mL), at0° C., was added tert-butyl nitrite (7.65 mL, 63.82 mmol) followed by 4N hydrochloric acid in 1,4-dioxane (1.91 mL, 7.66 mmol). The reactionmixture was allowed to warm to room temperature and stirred for 8 h. Themixture was concentrated under reduced pressure. The residue was dilutedwith aq. NaHCO₃ and extracted into DCM. The combined organic layers weredried, and the solvent was removed under reduced pressure. Purification(FCC, SiO₂, 0-20%, EtOAc/hexanes) afforded the title compound as a whitesolid (2.5 g, 54%). [M+H]=217.06219.05.

Step 3. 3-(3-(Difluoromethoxy)phenyl)-2-ethoxy-5-methylpyrazine. Asolution of 3-bromo-2-ethoxy-5-methylpyrazine (1.80 g, 8.29 mmol),3-(difluoromethoxy)phenyl)boronic acid (2.03 g, 10.78 mmol),tetrakis(triphenylphosphine) palladium(0) (958.25 mg, 0.83 mmol), sodiumcarbonate (21.63 mL, 1.15 mol/L, 24.88 mmol), in EtOH (22 mL) andtoluene (118 mL), under nitrogen, was heated at 88° C. for 1 h. Thereaction mixture was extracted with EtOAc. The combined organic layerswere dried (Na₂SO₄), and the solvent was removed under reduced pressure.Purification (FCC, SiO₂, O-50%, EtOAc/hexanes) afforded the titlecompound as a colorless oil (2.09 g, 90%). [M+H]=281.19.

Step 4. 5-(Bromomethyl)-3-(3-(difluoromethoxy)phenyl)-2-ethoxypyrazine.To a solution of 3-(3-(difluoromethoxy)phenyl)-2-ethoxy-5-methylpyrazine(2.00 g, 0.01 mol), 1-bromopyrrolidine-2,5-dione (1.27 g, 0.01 mol) incarbon tetrachloride (24 mL), was added benzoylperoxide (0.26 g, 1.07mmol). The mixture was heated at 88° C. for 8 h. The reaction mixturewas diluted with water and extracted with DCM. The combined organiclayers were dried (Na₂SO₄) and the solvent was removed under reducedpressure. Purification (FCC, SiO₂, 0-5%, EtOAc/hexanes) afforded thetitle compound contaminated with 10% starting material (1.5 g, 59%).[M+H]=459.13361.13.

Intermediates 2-3 were prepared in a manner analogous to Intermediate 1,Steps 3-4, with the appropriated starting material substitutions.

Intermediate 2. 5-(Bromomethyl)-3-(3-chlorophenyl)-2-methoxypyridine

M+H]=312.05314.04

Intermediate 3. 5-(Bromomethyl)-3-(3-chlorophenyl)-2-methoxypyrazine

[M+H]=313.17315.19

Intermediate 4. 3-Bromo-2-(difluoromethoxy)-5-methylpyridine

3-Bromo-2-(difluoromethoxy)-5-methylpyridine. To a solution of3-bromo-5-methylpyridin-2-ol (25.0 g, 0.13 mol) in ACN (100 mL) wasadded 2,2-difluoro-2-(fluorosulfonyl)acetic acid (23.7 g, 0.13 mol) andsodium carbonate (28.2 g, 0.270 mol). The reaction mixture was stirredat room temperature overnight. Water was added to the reaction mixture,and the reaction mixture was extracted with DCM. The combined organiclayers were dried (Na₂SO₄), and the solvent was removed under reducedpressure. Purification (FCC, SiO₂, 0-10%, EtOAc/hexanes) afforded thetitle compound as an off-white solid (22 g, 70%). M+H]=238.09240.09.

Intermediate 5.5-((1H-1,2,4-Triazol-1-yl)methyl)-3-bromo-2-(difluoromethoxy)pyridine

Step 1. 3-Bromo-5-(bromomethyl)-2-(difluoromethoxy)pyridine. To asolution of 3-bromo-2-(difluoromethoxy)-5-methylpyridine (0.50 g, 2.1mmol) in carbon tetrachloride (13 mL), was added1-bromopyrrolidine-2,5-dione (0.521 g, 2.93 mmol), andazobisisobutyronitrile (44 mg, 0.26 mmol). The reaction mixture wasstirred at 80° C. for 8 h. The reaction mixture was diluted with waterand extracted with DCM. The combined organic layers were dried (Na₂SO₄),and the solvent was removed under reduced pressure. Purification (FCC,SiO₂, 10-90%, EtOAc/hexanes) afforded the title compound (400 mg, 60%).[M+H]=317.88.

Step 2.5-((1H-1,2,4-Triazol-1-yl)methyl)-3-bromo-2-(difluoromethoxy)pyridine.To a solution of 3-bromo-5-(bromomethyl)-2-(difluoromethoxy)pyridine(Intermediate 4, 0.50 g, 1.57 mmol), in acetone (12 mL), was added1H-1,2,4-triazole (202 mg, 2.9 mmol), and potassium carbonate (650 mg,4.7 mmol). The reaction mixture stirred at room temperature for 2 h,then filtered and concentrated under reduced pressure. Purification(FCC, SiO₂, 30-70%, EtOAc/hexanes) afforded the title compound (431 mg,90%). [M+H]=304.91306.91.

Intermediate 6. 3-Bromo-2-ethoxy-5-methylpyridine

To a solution of 3-bromo-2-chloro-5-methylpyridine (4.00 g, 19.37 mmol)in ethanol (100 mL) was added sodium ethoxide (6.59 g, 96.9 mmol) inthree portions. The mixture was stirred under nitrogen at 100° C. for 2days. The reaction was cooled to room temperature, diluted with waterand extracted with DCM. The combined organic layers were dried (Na₂SO₄),and the solvent was removed under reduced pressure. Purification (FCC,SiO₂, 20%, EtOAc/hexanes) afforded the title compound (3.00 g, 72%). ¹HNMR (400 MHz, DMSO-d₆) δ 7.94 (dd, J=0.8, 2.3 Hz, 1H), 7.89-7.82 (m,1H), 4.31 (q, J=7.0 Hz, 2H), 2.18 (t, J=0.8 Hz, 3H), 1.30 (t, J=7.0 Hz,3H).

Intermediate 7. 5-Bromo-3-(3-chlorophenyl)-2-methoxypyridine

Step 1. 5-(3-Chlorophenyl)-6-methoxypyridin-3-amine. A 10 mL microwavevial was charged with 5-bromo-6-methoxypyridin-3-amine (2.00 g, 10 mmol)(3-chlorophenyl)boronic acid (1.87 g, 12 mmol),1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride DCM complex(365 mg, 0.45 mmol), ACN (6 mL) and saturated aq. sodium bicarbonate (3mL). The vial was sealed, purged with nitrogen and heated at 110° C. for15 min. The layers were separated and the aq. phase extracted withEtOAc. The combined organic layers were dried (Na₂SO₄), and the solventwas removed under reduced pressure. Purification (FCC, SiO₂, 0-50%,EtOAc/hexanes) afforded the title compound (1.95 g, 84%) which was takenon directly to the next step.

Step 2. 5-Bromo-3-(3-chlorophenyl)-2-methoxypyridine. A solution of5-(3-chlorophenyl)-6-methoxypyridin-3-amine (1.95 g, 8.39 mmol), copper(II) bromide (3.72 g, 16.7 mmol), tert-butyl nitrite (1.7 g, 16.7 mmol)in ACN (50 mL), under nitrogen, was heated at 60° C. for 12 h. Thereaction mixture was concentrated under reduced pressure. Purification(FCC, SiO₂, 0-10%, EtOAc/hexanes) afforded the title compound as anorange solid (1.53 g, 61%). [M+H]=298.20300.21.

Intermediate 8.3-(Chloromethyl)-5-(3-chlorophenyl)-6-methoxy-2-methylpyridine

Step 1. 6-Amino-5-bromo-2-methylnicotinonitrile. A solution of6-amino-2-methylnicotinonitrile (5 g, 37.6 mmol), NBS (7.36 g, 41.3mmol) and DCM (100 mL) was stirred at room temperature for 1 hr. Thereaction mixture was concentrated under reduced pressure. Purification(FCC, SiO₂, 1:1 EtOAc/DCM) afforded the title compound as tan solid (4.5g, 56%). [M+H]=211.95213.96.

Step 2. 5-Bromo-6-methoxy-2-methylnicotinonitrile. A solution of6-amino-5-bromo-2-methylnicotinonitrile (4.5 g, 21.2 mmol), HCl (2 mL 4N HCl in 1,4-dioxane), tert-butyl nitrite (6.56 g, 63.7 mmol) andmethanol (50 mL) was heated at 60° C. for 12 h. The solvent was removedunder reduced pressure. Purification (FCC, SiO₂, 0-25%, EtOAc/hexanes)afforded the title compound (2.5 g, 51%). [M+H]=226.96228.96.

Step 3. 5-(3-Chlorophenyl)-6-methoxy-2-methylnicotinonitrile. A 20 mLmicrowave vial was charged with5-bromo-6-methoxy-2-methylnicotinonitrile (1.2 g, 5.28 mmol),(3-chlorophenyl)boronic acid (990 mg, 6.3 mmol),1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride DCM complex(191 mg, 0.26 mmol), ACN (10 mL) and saturated aq. sodium bicarbonate (3mL). The vial was sealed, purged with nitrogen and heated at 100° C.under microwave irradiation for 10 min. The layers were separated andthe aq. phase extracted with EtOAc. The combined organic layers weredried (Na₂SO₄), and the solvent was removed under reduced pressure.Purification (FCC, SiO₂, 0-50%, EtOAc/hexanes) afforded the titlecompound as an off white solid (995 mg, 74%). [M+H]=259.06.

Step 4. 5-(3-Chlorophenyl)-6-methoxy-2-methylnicotinaldehyde. To acooled solution, −78° C., of5-(3-chlorophenyl)-6-methoxy-2-methylnicotinonitrile (500 mg, 1.9 mmol)in DCM (15 mL), under nitrogen, was added diisobutylaluminium hydride (1M in hexanes, 4.8 mL, 4.8 mmol) drop-wise, over 3 minutes. The reactionmixture was stirred at −78° C. for 1 h. The reaction was carefullyquenched by addition of saturated sodium fluoride (1 mL). After stirringfor 30 minutes the suspension was filtered and the filtrate concentratedunder reduced pressure. Purification (FCC, SiO₂, 0-50%, EtOAc/hexanes)afforded the title compound (358 mg, 72%). [M+H]=262.05.

Step 5. (5-(3-Chlorophenyl)-6-methoxy-2-methylpyridin-3-yl)methanol. Toa solution of 5-(3-chlorophenyl)-6-methoxy-2-methylnicotinaldehyde (350mg, 1.34 mmol) in methanol (3 mL) was added sodium borohydride (52 mg,1.3 mmol). The solution was stirred at room temperature for 20 minutesthen concentrated under reduced pressure. Purification (FCC, SiO₂,0-50%, EtOAc/hexanes) afforded the title compound (322 mg, 91%).[M+H]=264.06.

Step 6. 3-(Chloromethyl)-5-(3-chlorophenyl)-6-methoxy-2-methylpyridine.Into a scintillation vial containing(5-(3-chlorophenyl)-6-methoxy-2-methylpyridin-3-yl)methanol (340 mg,1.29 mmol) in DCM (5 mL), was added diisopropylethylamine (199 mg, 1.54mmol), and methanesulfonyl chloride (147 mg, 1.29 mmol). The solutionwas stirred at room temperature for 1 h. The reaction mixture wasextracted with water (3×). The combined organic layers were dried(Na₂SO₄), and the solvent was removed under reduced pressure.Purification (FCC, SiO₂, 0-30%, EtOAc/hexanes) afforded the titlecompound (87 mg, 24%). [M+H]=282.03

Intermediate 9.2-Difluoromethoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine

Step 1. 4-Bromo-2-(difluoromethoxy)pyridine. To a stirring solution of2-chloro-2,2-difluoroacetate (6.00 g, 39.4 mmol) in ACN (200 mL) wasadded 4-bromopyridin-2(1H)-one (4.90 g, 28.1 mmol). The mixture wasrefluxed for 8 h. The resulting mixture was filtered and the filtratewas extracted with hexane (6×20 mL). The combined organic layers weredried (Na₂SO₄), and concentrated at room temperature to give the titlecompound as a liquid (2.60 g, 42% yield). ¹H NMR (400 MHz, DMSO-d₆) δ8.19-8.20 (s, 1H), 7.48 (s, 1H), 7.52 (s, 1H), 7.54-7.88 (m, 1H).

Step 2.2-Difluoromethoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine.To a solution of 4-bromo-2-(difluoromethoxy)pyridine (7.20 g, 32.1mmol), in 1,4-dioxane (230 mL), was added bis(pinacolato)diboron (8.80g, 34.6 mmol), and potassium acetate (7.10 g, 71.9 mmol). The flask wasfitted with a reflux condenser and vacuum/nitrogen inlet, and it wasdegassed/backfilled with nitrogen (3×). The catalyst,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.35 g, 3.2mmol) was added, and the reaction mixture was refluxed for 8 h. Theresulting mixture was filtered, and concentrated under reduced pressure.Purification (FCC, SiO₂, 1:1 petroleum etherhexanes) afforded the titlecompound (6.10 g, 70%) as a liquid. ¹H NMR (400 MHz, DMSO-d₆) δ8.31-8.32 (d, J=4.8 Hz, 1H), 7.52-7.89 (m, 1H), 7.42-7.44 (d, J=4.8 Hz,1H), 7.156 (s, 1H), 1.32 (s, 12H).

Intermediate 10.5-(Bromomethyl)-2-(difluoromethoxy)-3-(3-(oxetan-3-yloxy)phenyl)pyridine

Step 1. 3-(2-(Difluoromethoxy)-5-methylpyridin-3-yl)phenol. A 20 mLmicrowave vial was charged with3-bromo-2-(difluoromethoxy)-5-methylpyridine (intermediate 4, 1.90 g,7.98 mmol), 3-hydroxyphenylboronic acid (1.32 g, 9.58 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (330 mg,0.40 mmol), sodium carbonate (2.12 g, 19.96 mmol), water (4.0 mL), andACN (12 mL). The vial was sealed, purged with nitrogen, and heated undermicrowave irradiation at 100° C. for 15 min. The reaction mixture wasdiluted with water and extracted with DCM (3×). The combined organicphase was dried (Na₂SO₄), filtered, and concentrated under reducedpressure. Purification (FCC, SiO₂, 0-40% EtOAc/hexanes) afforded thetitle compound (1.81 g, 91%) as a colorless waxy solid. [M+H]=252.12.

Step 2.2-(Difluoromethoxy)-5-methyl-3-(3-(oxetan-3-yloxy)phenyl)pyridine. To asolution of 3-(2-(difluoromethoxy)-5-methylpyridin-3-yl)phenol (502.5mg, 2.0 mmol), in DMF, was added oxetan-3-yl 4-methylbenzenesulfonate(685 mg, 3.0 mmol), and potassium carbonate (553 mg, 4.00 mmol). Thereaction mixture was stirred at 60° C. for 8 h. LC-MS suggested about50% conversion. The temperature was raised to 90° C. and the reactionmixture was stirred an additional 4 h. Sat. aq. NaCl was added, and themixture was extracted with DCM (3×). The combined organic layers weredried (Na₂SO₄), filtered and concentrated under reduced pressure.Purification (FCC, SiO₂, 10-30% EtOAc/hexanes) afforded the titlecompound (310 mg, 50%) as a colorless solid. [M+H]=308.11

Step 3.5-(Bromomethyl)-2-(difluoromethoxy)-3-(3-(oxetan-3-yloxy)phenyl)pyridine.To a solution of2-(difluoromethoxy)-5-methyl-3-(3-(oxetan-3-yloxy)phenyl)pyridine (310mg, 1.0 mmol) in carbon tetrachloride (10 mL), was added1-bromopyrrolidine-2,5-dione (180 mg, 1.0 mmol), and benzoylperoxide (37mg, 0.15 mmol). The reaction mixture was stirred at 80° C. for 8 h. Thereaction mixture was diluted with water and extracted with DCM. Thecombined organic layers were dried (Na₂SO₄), and the solvent was removedunder reduced pressure. Purification (FCC, SiO₂, 10-30%, EtOAc/hexanes)afforded the title compound (140 mg, 36%). [M+H]=387.21

Intermediate 11.5-(Bromomethyl)-2-(difluoromethoxy)-3-(3-isopropoxyphenyl)pyridine

The title compound was prepared in a manner analogous to Intermediate10, using 2-bromopropane for step 2, followed by bromination accordingto step 3. [M-FI-1]=373.24.

Intermediate 12.5-(Bromomethyl)-3-(3-chlorophenyl)-2-(difluoromethoxy)pyridine

The title compound was prepared in a manner analogous to Intermediate10, using Intermediate 4 and 3-chlorophenyl boronic acid in Step 1,followed by bromination according to Step 3. [M+H]=348.17350.15

Intermediate 13.5-((1H-1,2,4-Triazol-1-yl)methyl)-3-bromo-2-methoxypyridine

The title compound was prepared in a manner analogous to Intermediate 5,with the appropriate starting material substitutions. [M+H]=269.21271.23

EXAMPLES Example 15-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyrimidine-2-carbonitrile

Into a 5 mL microwave vial was combined5-(bromomethyl)-3-(3-(difluoromethoxy)phenyl)-2-ethoxypyrazine(Intermediate 1, 176.00 mg, 0.49 mmol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2-carbonitrile(124.55 mg, 0.54 mmol), EtOH (2.45 mL), benzene (7.00 mL),tetrakis(triphenylphosphine)palladium(0) (56.63 mg, 0.05 mmol), andsodium bicarbonate (1.38 mL, 1.15 mol/L; 1.59 mmol). The vial wassealed, purged with nitrogen and heated to 125° C. under microwaveconditions for 15 minutes. Water was removed from the reaction with apipette, and the crude reaction mixture was filtered thru CELITE®, andwashed with EtOAc (3×5 mL). The combined organic layers were dried(Na₂SO₄), and the solvent was removed under reduced pressure.Purification (FCC, SiO₂, 0-30%, EtOAc/hexanes) afforded the titlecompound as a white solid (100 mg, 53%). ¹H NMR (400 MHz, CD₃OD) δ 8.94(s, 2H), 8.17 (s, 1H), 7.95-7.90 (m, 1H), 7.85 (t, J=1.8 Hz, 1H), 7.46(t, J=8.2 Hz, 1H), 7.19 (dd, J=2.3, 7.8 Hz, 1H), 7.04-6.61 (m, 1H), 4.49(q, J=7.0 Hz, 2H), 4.30-4.25 (m, 2H), 1.44 (t, J=7.0 Hz, 3H).[M+H]=384.15.

Example 22-Chloro-5-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine

To a solution of 5-(bromomethyl)-3-(3-chlorophenyl)-2-methoxypyridine(Intermediate 2, 100 mg, 0.321 mmol), (2-chloropyrimidin-5-yl)boronicacid (76 mg, 0.481 mmol) in ACN (3.2 mL) was added NaHCO₃ (417 mg, 1.282mmol) and PdCl₂(dppf)-DCM (23 mg, 0.032 mmol). The reaction was heatedunder microwave conditions, at 120° C. for 12 minutes. Water was removedfrom the reaction with a pipette, and the crude reaction mix wasfiltered thru CELITE®, and washed with EtOAc. The combined organics weredried (Na₂SO₄), filtered and concentrated onto silica. Purification(FCC, SiO2, 30-70% EtOAc/hexanes) afforded the title compound (61 mg,55%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.34 (s, 2H), 8.11 (d, J=2.0 Hz, 1H),7.70 (d, J=2.0 Hz, 1H), 7.58 (t, J=1.8 Hz, 1H), 7.53-7.36 (m, 3H), 3.83(s 2H), 3.73 (s, 3H). [M+H]=346.11.

Example 3{2-[(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)amino]ethyl}dimethylamine

A 5 mL microwave vial was charged with2-chloro-5-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine(Example 2, 50.00 mg, 0.14 mmol), ACN (1.44 mL),N1,N1-dimethylethane-1,2-diamine (0.03 mL, 0.29 mmol), andN-ethyl-N-isopropylpropan-2-amine (77.13 μL, 0.43 mmol). The vial wassealed, and the reaction mixture was heated at 180° C. for 15 minutes.EtOAc (5 mL) was added to the reaction mixture, and the reaction mixturewas extracted with water (3×). The combined organic layers were dried(Na₂SO₄), and the solvent was removed under reduced pressure.Purification (FCC, SiO₂, 0-15% MeOH/DCM) afforded the title compound(15.6 mg, 28%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.21 (s, 2H), 8.09 (s, 1H),7.67 (br s, 2H), 7.58 (s, 1H), 7.51-7.34 (m, 2H), 6.79 (br s, 1H), 3.84(s, 3H), 3.72 (s, 2H), 2.42-2.37 (m, 4H), 2.17 (s, 6H). [M+H]=398.20.

Example 42-Methoxy-3-(6-methoxypyridin-2-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine

A solution of5-((1H-1,2,4-triazol-1-yl)methyl)-3-bromo-2-(difluoromethoxy)pyridine(Intermediate 13, 50 mg, 0.16 mmol), (6-methoxypyridin-2-yl)boronic acid(46 mg, 0.30 mmol), in EtOH (2.45 mL), benzene (7.00 mL), was combinedwith tetrakis(triphenylphosphine)palladium(0) (27 mg, 0.02 mmol), and 4M aqueous sodium carbonate (3 mL) in a microwave vial. The vial wassealed, purged with nitrogen and heated under microwave conditions to120° C. for 12 minutes. Water was removed from the reaction with apipette, and the crude reaction mix was filtered thru CELITE®, andwashed with EtOAc (3×5 mL). The combined organic layers were dried(Na₂SO₄), and the solvent was removed under reduced pressure.Purification (FCC, SiO₂, 30-70% EtOAc/hexanes) afforded the titlecompound (11.9 mg, 25%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.88 (s, 1H), 7.58(d, J=2.7 Hz, 1H), 7.41 (d, J=2.3 Hz, 1H), 7.24 (s, 1H), 6.91-6.84 (m,2H), 5.93 (d, J=4.3 Hz, 1H), 4.69 (s, 2H), 3.97 (s, 3H), 3.14 (s, 3H).[M+H]=298.02.

Examples 5-12 were prepared analogous to procedures described inExamples 1 or 2, with the appropriate starting materials and reagentsubstitutions.

Example 52-Methoxy-3-(3-methylphenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine

¹H NMR (400 MHz, DMSO-d₆) δ 8.65 (s, 1H), 8.18-8.15 (m, 1H), 7.95 (s,1H), 7.70 (d, J=2.3 Hz, 1H), 7.31-7.27 (m, 3H), 7.19-7.14 (m, 1H), 5.41(s, 2H), 3.85 (s, 3H), 2.33 (s, 3H). [M+H]=281.36.

Example 62-Methoxy-3-(5-methylpyridin-3-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine

¹H NMR (400 MHz, DMSO-d₆) δ 8.93 (s, 1H), 8.77 (s, 2H), 8.57 (s, 1H),8.35 (d, J=2.0 Hz, 1H), 8.04 (s, 2H), 5.45 (s, 2H), 3.91 (s, 3H), 2.50(s, 3H). [M+H]=282.09.

Example 72-Methoxy-3-(2-methylpyridin-4-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine

¹H NMR (400 MHz, DMSO-d₆) δ 8.77-8.63 (m, 2H), 8.37 (d, J=2.3 Hz, 1H),8.04 (d, J=2.0 Hz, 1H), 8.00-7.85 (m, 2H), 7.58-7.43 (m, 1H), 5.45 (s,2H), 3.92 (s, 3H), 2.68 (s, 3H). [M+H]=282.20.

Example 8{3-[2-Methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridin-3-yl]phenyl}methanol

¹H NMR (400 MHz, DMSO-d₆) δ 8.65 (s, 1H), 8.18 (d, J=2.0 Hz, 1H), 7.95(s, 1H), 7.70 (d, J=2.3 Hz, 1H), 7.45-7.26 (m, 4H), 5.41 (s, 2H), 5.22(t, J=5.7 Hz, 1H), 4.51 (d, J=5.9 Hz, 2H), 3.85 (s, 3H). [M+H]=297.23.

Example 93-(3-Methanesulfonylphenyl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.61 (s, 1H), 8.24 (d, J=1.96 Hz, 1H), 8.12(s, 1H), 8.00 (s, 1H), 7.94 (d, J=7.83 Hz, 1H), 7.89 (d, J=7.83 Hz, 1H),7.83 (d, J=1.56 Hz, 1H), 7.65-7.72 (m, 1H), 5.46 (s, 2H), 3.96 (s, 3H),3.15 (s, 3H). [M+H]=345.21.

Example 102-Methoxy-3-(4-methylpyridin-2-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.60 (s, 1H), 8.44 (d, J=5.1 Hz, 1H), 8.26 (d,J=2.3 Hz, 1H), 8.01 (d, J=2.3 Hz, 1H), 7.98 (s, 1H), 7.70 (s, 1H), 7.22(d, J=5.1 Hz, 1H), 5.46 (s, 2H), 3.99 (s, 3H), 2.42 (s, 3H).[M+H]=282.31.

Example 112-Methoxy-3-(6-methylpyridin-2-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.50 (s, 1H), 8.32-8.27 (m, 1H), 8.22 (d,J=2.3 Hz, 1H), 7.89 (s, 1H), 7.68-7.62 (m, 1H), 7.56 (d, J=2.7 Hz, 1H),7.26 (dd, J=5.1, 7.8 Hz, 1H), 5.37 (s, 2H), 3.82 (s, 3H), 2.04 (s, 3H).[M+H]=282.39.

Example 122-(Difluoromethoxy)-3-(3-methylphenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine

As a mixture of compounds, ¹H NMR (400 MHz, DMSO-d₆) δ 8.72-8.61 (m,1H), 8.00-7.96 (m, 1H), 7.94-7.86 (m, 1H), 7.73-7.68 (m, 1H), 7.55-7.51(m, 1H), 7.40-7.33 (m, 1H), 7.32-7.27 (m, 1H), 7.24 (d, J=7.8 Hz, 1H),5.75 (s, 1H), 5.49 (s, 1H), 5.44 (s, 1H), 2.35 (s, 3H). [M+H]=317.15.

Example 135-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyrimidine-2-carboxamide

To a solution of5-((6-(3-(difluoromethoxy)phenyl)-5-ethoxypyrazin-2-yl)methyl)pyrimidine-2-carbonitrile(Example 1, 100.00 mg, 0.26 mmol) in MeOH (1.3 mL) was added aq. NaOH(0.78 mL, 0.78 mmol), followed by hydrogen peroxide (0.78 mL, 0.79 mmol)The reaction mixture was stirred at room temperature for 8 h. Thereaction mixture was concentrated, and the precipitate filtered andwashed with water to obtain the title compound as a white solid (70 mg,67%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.93 (s, 2H), 8.27 (s, 1H), 8.12 (brs, 1H), 7.91-7.84 (m, 1H), 7.81 (t, J=1.8 Hz, 1H), 7.72 (br s, 1H), 7.52(s, 1H), 7.44-7.02 (m, 2H), 4.42 (q, J=7.0 Hz, 2H), 4.25 (s, 2H), 1.35(t, J=7.0 Hz, 3H). [M+H]=402.26.

Example 14[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methanol

To a cooled solution, −78° C., of5-bromo-3-(3-chlorophenyl)-2-methoxypyridine (Intermediate 7, 1.5 g, 5mmol) in THF (25 mL), under nitrogen, was added nBuLi (4.8 mL, 5.5 mmol)drop-wise over 2 minutes. The reaction mixture was stirred at −78° C.for 40 min. A solution of 4-fluorobenzaldehyde (744 mg, 6 mmol) in THF(2 mL) was added, and the reaction mixture was stirred an additional 30min at −78° C. The reaction was quenched with saturated sodium sulfate,filtered, and concentrated under reduced pressure. Purification (FCC,SiO₂, 0-25% EtOAc/hexanes) afforded the title compound as a colorlesssolid (1.65 g, 96%). ¹H NMR (400 MHz, CD₃OD) δ 8.11 (d, J=2.3 Hz, 1H),7.63 (d, J=2.0 Hz, 1H), 7.51 (s, 1H), 7.47-7.29 (m, 5H), 7.07 (t, J=8.6Hz, 2H), 5.84 (s, 1H), 3.93 (s, 3H). [M+H]=344.18.

Examples 15-16 were prepared in a manner analogous to Example 14, withthe appropriate starting materials and reagent substitutions.

Example 151-[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]-1-(4-fluorophenyl)ethan-1-ol

¹H NMR (400 MHz, CD₃OD) δ 8.16 (d, J=2.7 Hz, 1H), 7.68 (d, J=2.7 Hz,1H), 7.53-7.43 (m, 3H), 7.42-7.28 (m, 3H), 7.04 (t, J=8.8 Hz, 2H), 3.93(s, 3H), 1.94 (s, 3H). [M+H]=358.21.

Example 16[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl](5-fluoropyridin-2-yl)methanol

¹H NMR (400 MHz, CD₃OD) δ 8.38 (d, J=2.7 Hz, 1H), 8.16 (d, J=2.3 Hz,1H), 7.77-7.58 (m, 3H), 7.52 (s, 1H), 7.45-7.28 (m, 3H), 5.87 (s, 1H),3.93 (s, 3H). [M+H]=345.19.

Example 17{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methyl}(methyl)amine

Step 1.5-(Chloro(4-fluorophenyl)methyl)-3-(3-chlorophenyl)-2-methoxypyridine.To a cooled solution, 0° C., of[5-(3-chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methanol(Example 14, 1.43 g, 4.17 mmol), in DCM (10 mL), was added thionylchloride (744 mg, 6.25 mmol) dropwise. The solution was allowed to warmup to room temperature, and stirred for 1 h. The reaction mixture wasconcentrated under reduced pressure. Purification (FCC, SiO₂, 0-10%EtOAc/hexanes) afforded the title compound, which was used directly forthe next step.

Step 2.{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methyl}(methyl)amine.To a solution of5-(chloro(4-fluorophenyl)methyl)-3-(3-chlorophenyl)-2-methoxypyridine(70 mg, 0.193 mmol) in ACN (2 mL) was added potassium carbonate (53 mg,0.39 mmol), sodium Iodide (5 mg, 0.03 mmol), and methylamine (0.5 mL,0.97 mmol). The reaction was sealed and heated at 45° C. for 12 h. Thereaction mixture was concentrated. Purification (FCC, SiO₂, 0-10%MeOH/DCM) afforded the title compound (23 mg, 33%). ¹H NMR (400 MHz,CD₃OD) δ 8.20 (d, J=2.3 Hz, 1H), 7.71 (s, 1H), 7.50-7.42 (m, 3H),7.40-7.27 (m, 3H), 7.18 (t, J=8.8 Hz, 2H), 5.54-5.49 (m, 1H), 3.90 (s,3H), 2.63 (s, 3H). [M⁺; loss of NHMe]=326.14.

Examples 18-19 were prepared in a manner analogous to Example 17, withthe appropriate starting materials and reagent substitutions.

Example 18[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methanamine

¹H NMR (400 MHz, CD₃OD) δ 8.17 (d, J=2.3 Hz, 1H), 7.72 (d, J=2.7 Hz,1H), 7.55 (s, 1H), 7.49-7.34 (m, 5H), 7.18 (m, 2H), 5.58 (s, 1H), 3.96(s, 3H). [M⁺; loss of NH₂]=326.14.

Example 19{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methyl}dimethylamine

¹H NMR (400 MHz, CD₃OD) δ 8.28 (d, J=2.3 Hz, 1H), 7.86 (s, 1H), 7.57(dd, J=5.1, 8.6 Hz, 2H), 7.50 (t, J=1.6 Hz, 1H), 7.43-7.28 (m, 3H), 7.18(m, 2H), 5.51-5.38 (m, 1H), 3.90 (s, 3H), 2.88-2.74 (m, 6H).[M+H]=371.20.

Example 203-(3-Chlorophenyl)-5-[fluoro(4-fluorophenyl)methyl]-2-methoxypyridine

To a solution of[5-(3-chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methanol(Example 14, 70 mg, 0.18 mmol) in DCM (1 mL) was added Deoxo-Fluor® (79mg, 0.36 mmol). The solution was stirred at room temperature for 1 hthen concentrated under reduced pressure. Purification (FCC, SiO₂, 0-10%EtOAc/hexanes) afforded the title compound (21 mg, 34%). ¹H NMR (400MHz, CD₃OD) δ 8.13 (s, 1H), 7.62 (d, J=2.0 Hz, 1H), 7.52 (s, 1H),7.47-7.31 (m, 5H), 7.15 (t, J=8.8 Hz, 2H), 6.70-6.52 (m, 1H), 3.96 (s,3H). [M+H]=346.17.

Example 21 4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}benzoicacid

Step 1. Methyl4-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)benzoate wasprepared in a manner analogous to Example 2 with the appropriatestarting material substitution. Purification (FCC, SiO₂, 0-50%EtOAc/hexanes) afforded the title compound. [M+H]=368.11

Step 2. 4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}benzoicacid. To a solution of methyl4-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)benzoate (91 mg,0.248 mmol) in MeOH (2 mL) was added 2 N aq. NaOH (2.0 mL). The reactionmixture was stirred at rt for 2 hr. Solvent was removed under reducedpressure, and the resulting solid was triturated with diethyl ether. Theresulting white solid was dissolved in DCM and filtered to removeinorganic solids. The filtrated was concentrated under reduced pressureto afford the title compound (74 mg, 85%). ¹H NMR (400 MHz, CD₃OD) δ8.03 (d, J=2.0 Hz, 1H), 7.96 (d, J=7.8 Hz, 2H), 7.60 (d, J=2.3 Hz, 1H),7.52 (s, 1H), 7.43-7.30 (m, 5H), 4.05 (s, 2H), 3.95 (s, 3H).[M+H]=354.13.

Example 225-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}pyrimidine-2-carbonitrile

Example 22 was prepared in a manner analogous to Example 1, with theappropriate starting materials and reagent substitutions. [M+H]=338.10

Example 235-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxylicacid

A solution of5-{[6-(3-chlorophenyl)-5-methoxypyrazin-2-yl]methyl}pyrimidine-2-carbonitrile(Example 22, 30 mg, 0.0845 mmol) in MeOH (1.54 mL) was heated to 50° C.until the starting material dissolved. 1 N aq. NaOH (0.23 mL, 0.23 mmol)was added followed by hydrogen peroxide (0.23 mL, 1.00 mol/L, 0.23 mmol)and the solution was heated at 50° C. for an additional 2 h. Water (5mL) was added and the reaction was filtered and washed with water (3×5mL). A mixture of products were observed;5-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxylicacid (the title compound) and5-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxamide(Example 24, 4 mg, 13%). The filtrated contained the acid, and the waterlayer was acidified with concentrated HCl (3 drops) and extracted withDCM (3×20 mL). The organic layers were combined, dried (Na₂SO₄), andconcentrated under reduced pressure to afford the title compound (23 mg,74%). ¹H NMR (400 MHz, CD₃OD) δ 8.86 (br s, 2H), 8.11 (d, J=1.96 Hz,1H), 7.66 (d, J=1.96 Hz, 1H), 7.55 (s, 1H), 7.49-7.27 (m, 3H), 4.14 (brs, 2H), 3.94 (s, 3H). [M+H]=356.13

Example 245-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxamide

The title compound was made in a manner analogous to Example 13. ¹H NMR(400 MHz, CD₃OD) δ 8.83 (s, 2H), 8.11 (d, J=2.0 Hz, 1H), 7.65 (d, J=2.3Hz, 1H), 7.54 (s, 1H), 7.47-7.29 (m, 3H), 4.12 (s, 2H), 3.94 (s, 3H).[M+H]=355.21.

Examples 25, 27-30, 32-35, 37-43. 45-89, 91-108 were prepared analogousto procedures described in Examples 1 or 2, with the appropriatestarting materials and reagent substitutions.

Example 255-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine

¹H NMR (400 MHz, CD₃OD) δ 8.18 (s, 2H), 8.02 (d, J=2.3 Hz, 1H),7.58-7.51 (m, 2H), 7.44-7.31 (m, 3H), 3.93 (s, 3H), 3.82 (s, 2H).[M+H]=327.21.

Example 26(4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)urea

Step 1. 3-(3-Chlorophenyl)-2-methoxy-5-(4-nitrobenzyl)pyridine. Thetitle compound was prepared in a manner analogous to Example 1, fromIntermediate 2 and 4-nitrophenyl boronic acid to afford a tan solid.[M+H]=355.07.

Step 2. 4-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)aniline. Asolution of 3-(3-chlorophenyl)-2-methoxy-5-(4-nitrobenzyl)pyridine (162mg, 0.45 mmol), HOAc (3 mL), water (1 mL), and zinc (292.5 mg, 4.5 mmol)was heated at 60° C. for 1 h, then filtered hot through a 1 cm pad ofCelite® and used directly for the next step.

Step 3.(4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)urea.4-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)aniline solutionfrom Step 2 was added potassium cyanate (73 mg, 0.9 mmol). The mixturewas sonicated for 20 min to afford a gummy ppt. The reaction mixture wasdiluted with water, neutralized with aq. sodium carbonate to pH 7, thenextracted with EtOAc (3×5 mL). The combined organic layers wereconcentrated under reduced pressure to afford a solid, which wastriturated with DCM to give (55 mg, 34%) of the title compound as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.41 (s, 1H), 8.06 (d, J=2.3Hz, 1H), 7.64-7.53 (m, 2H), 7.49-7.37 (m, 3H), 7.28 (d, J=8.2 Hz, 2H),7.10 (d, J=8.6 Hz, 2H), 5.75 (s, 2H), 3.85-3.81 (m, 5H). [M+H]=368.27.

Example 27 4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}benzamide

¹H NMR (400 MHz, CD₃OD) δ 8.02 (d, J=2.0 Hz, 1H), 7.81 (d, J=8.2 Hz,2H), 7.56-7.49 (m, 2H), 7.42-7.29 (m, 5H), 4.03 (s, 2H), 3.92 (s, 3H).[M+H]=353.13.

Example 285-((1H-Pyrazol-4-yl)methyl)-3-(3-chlorophenyl)-2-(difluoromethoxy)pyridine

¹H NMR (400 MHz, DMSO-d₆) δ 12.61 (br s, 1H), 7.92-7.43 (m, 9H), 3.84(s, 2H). [M+H]=336.18.

Example 295-{[6-(Difluoromethoxy)-5-(3-methoxyphenyl)pyridin-3-yl]methyl}pyrimidin-2-amine

¹H NMR (400 MHz, CD₃OD) δ 8.19 (s, 2H), 8.07 (d, J=2.35 Hz, 1H), 7.71(d, J=1.96 Hz, 1H), 7.57 (s, 1H), 7.30-7.38 (m, 1H), 7.02-7.10 (m, 2H),6.95 (dd, J=8.22, 1.57 Hz, 1H), 3.82 (s, 3H), 3.87 (s, 2H).[M+H]=359.28.

Example 305-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridin-2-amine

¹H NMR (400 MHz, CD₃OD) δ 7.99 (d, J=2.0 Hz, 1H), 7.80 (d, J=2.0 Hz,1H), 7.52 (d, J=2.0 Hz, 2H), 7.43-7.29 (m, 4H), 6.55 (d, J=8.6 Hz, 1H),3.92 (s, 3H), 3.81 (s, 2H). [M+H]=326.26.

Example 311-(4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)-3-(oxetan-3-yl)urea

To a solution of4-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)benzoic acid(Example 21, 90 mg, 0.25 mmol) in toluene (5 mL) was addedN,N-diisopropylethylamine (33 mg, 0.25 mmol) and diphenylphosphorylazide (77 mg, 0.28 mmol). The mixture was stirred at 80° C. for 30minutes. The LCMS confirmed the disappearance of the starting acid. Asolution of oxetan-3-amine hydrochloride (41.5 mg, 0.38 mmol),N,N-diisopropylethylamine (49 mg, 0.38 mmol) and DCM (2 mL) was added tothe reaction mixture and stirred at room temperature for 2 h. The LCMSconfirmed the presence of the product. All solvents were removed underreduced pressure. Purification (FCC, SiO₂, 0-5%, MeOH/DCM) afforded thetitle compound (50 mg, 46%). ¹H NMR (400 MHz, CD₃OD) δ 7.99 (d, J=2.3Hz, 1H), 7.49 (d, J=2.3 Hz, 2H), 7.41-7.24 (m, 5H), 7.14 (d, J=8.6 Hz,2H), 4.87 (br s, 3H), 4.55 (s, 2H), 3.91 (s, 3H), 3.90 (s, 2H).[M+H]=424.20.

Example 323-(3-Chlorophenyl)-2-methoxy-5-[(6-methoxypyridin-3-yl)methyl]pyridine

¹H NMR (400 MHz, DMSO-d₆) δ 8.10 (dd, J=2.0, 6.3 Hz, 2H), 7.67 (d, J=2.3Hz, 1H), 7.61-7.54 (m, 2H), 7.50-7.36 (m, 3H), 6.72 (d, J=8.2 Hz, 1H),3.86 (s, 2H), 3.84 (s, 3H), 3.78 (s, 3H). [M+H]=341.19.

Example 335-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridin-2-amine

¹H NMR (400 MHz, CD₃OD) δ 8.06 (d, J=2.3 Hz, 1H), 7.77 (dd, J=2.0, 9.4Hz, 1H), 7.73-7.64 (m, 2H), 7.51-7.30 (m, 5H), 6.89 (d, J=9.4 Hz, 1H),3.88 (s, 2H). [M+H]=362.31.

Example 345-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N,N-dimethylpyridin-2-amine

¹H NMR (400 MHz, CD₃OD) δ 8.00 (d, J=2.0 Hz, 1H), 7.94 (d, J=2.0 Hz,1H), 7.51 (d, J=1.6 Hz, 2H), 7.43-7.29 (m, 4H), 6.63 (d, J=9.0 Hz, 1H),3.92 (s, 3H), 3.84 (s, 2H), 3.04 (s, 6H). [M+H]=354.22.

Example 355-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyrimidine-2-carbonitrile

¹H NMR (400 MHz, CD₃OD) δ 8.85 (s, 2H), 8.18 (s, 1H), 7.85 (d, J=2.3 Hz,1H), 7.80-7.38 (m, 5H), 4.21-4.17 (m, 2H). [M+H]=373.14.

Example 365-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1,3-thiazol-2-amine

Step 1. 3-(3-Chlorophenyl)-5-(dibromomethyl)-2-(difluoromethoxy)pyridinewas prepared in a manner analogous to Intermediate 1, Steps 4, with theappropriate starting material substitutions. [M+H]=426.1, 428.1, 430.1.

Step 2. 5-(3-Chlorophenyl)-6-(difluoromethoxy)nicotinaldehyde. To asolution of3-(3-chlorophenyl)-5-(dibromomethyl)-2-(difluoromethoxy)pyridine (700mg, 1.65 mmol) in ACN (2 mL) was added a solution of sodium carbonate(525 mg, 5.0 mmol) in water (4 mL) and the mixture was stirred at 70° C.for 16 h. The LCMS showed complete conversion. All solvents were removedunder reduced pressure. The residue was dissolved in DCM, washed withwater, dried (Na₂SO₄), filtered and the solvent was removed underreduced pressure. Purification (FCC, SiO₂, 0-20%, EtOAc/hexanes)afforded 5-(3-chlorophenyl)-6-(difluoromethoxy)nicotinaldehyde (355 mg,76%). [M+H]=284.1.

Step 3. tert-Butyl(5-((5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)(hydroxy)methyl)thiazol-2-yl)carbamate.A solution of tert-butyl (5-bromothiazol-2-yl)carbamate (100 mg, 0.36mmol) in THF (2 mL) was cooled to −78° C. and n-butyllithium (0.51 mL of1.4 M solution in hexanes, 0.72 mmol) was added dropwise and the mixturewas stirred for 30 minutes at −78° C. A solution of5-(3-chlorophenyl)-6-(difluoromethoxy)nicotinaldehyde (112 mg, 0.39mmol) in THF (2 mL) was added dropwise to the reaction and this mixturewas stirred for 30 minutes at −78° C. The LCMS confirmed the product. Asaturated aqueous solution of ammonium chloride was added and themixture was extracted into EtOAc. The combined extracts were dried(Na₂SO₄), filtered and solvent was removed under reduced pressure.Purification (FCC, SiO₂, 10-80%, EtOAc/hexanes) afforded tert-butyl(5-((5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)(hydroxy)methyl)thiazol-2-yl)carbamate(73 mg, 42%). [M(-tBu)+H]=428.1.

Step 4.5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1,3-thiazol-2-amine.To a solution of tert-butyl(5-((5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)(hydroxy)methyl)thiazol-2-yl)carbamate(73 mg, 0.15 mmol) in DCM (3 mL) was added triethylsilane (52.2 mg, 0.45mmol) and TFA (102 mg, 0.90 mmol) and the mixture was stirred at roomtemperature for 16 h. The LCMS showed complete conversion. All solventswere removed in vacuo. The residue was dissolved in DCM and a saturatedaqueous solution of sodium bicarbonate, the layers shaken and separatedand the aqueous layer extracted into DCM. The combined organic extractswere washed with brine, dried (Na₂SO₄), filtered and solvent underreduced pressure. Purification (FCC, SiO₂, 20-100%, EtOAc/hexanes) gavethe title compound (34.4 mg, 62%). ¹H NMR (400 MHz, CD₃OD) δ 8.02 (d,J=2.3 Hz, 1H), 7.71-7.30 (m, 6H), 6.68 (s, 1H), 3.94 (s, 2H).[M+H]=368.06.

Example 37(2-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)methanol

¹H NMR (400 MHz, CD₃OD) δ 7.94 (d, J=2.3 Hz, 1H), 7.49 (m, 2H),7.44-7.14 (m, 7H), 4.63 (s, 2H), 4.07 (s, 2H), 3.91 (s, 3H).[M+H]=340.13.

Example 385-{[5-(3-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine

¹H NMR (400 MHz, CD₃OD) δ 8.17 (s, 2H), 8.02 (d, J=2.3 Hz, 1H), 7.57 (d,J=2.3 Hz, 1H), 7.43-7.25 (m, 3H), 7.09-7.02 (m, 1H), 3.93 (s, 3H), 3.81(s, 2H). [M+H]=311.00.

Example 395-{[5-(3-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carbonitrile

¹H NMR (400 MHz, CDCl₃) δ 8.71 (s, 2H), 8.06 (d, J=2.3 Hz, 1H), 7.55 (s,1H), 7.42-7.35 (m, 2H), 7.26-7.23 (m, 1H), 7.10-7.03 (m, 1H), 4.05 (s,2H), 3.98 (s, 3H). [M+H]=321.17.

Example 405-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}pyrimidin-2-amine

¹H NMR (400 MHz, CD₃OD) δ 8.18 (s, 2H), 7.99 (d, J=2.3 Hz, 1H), 7.56 (d,J=2.3 Hz, 2H), 7.47-7.30 (m, 3H), 4.38 (d, J=7.0 Hz, 2H), 3.81 (s, 2H),1.33 (t, J=7.0 Hz, 3H). [M+H]=341.04.

Example 415-{[5-(3-Chlorophenyl)-6-(propan-2-yloxy)pyridin-3-yl]methyl}pyrimidin-2-amine

¹H NMR (400 MHz, CD₃OD) δ 8.18 (s, 2H), 8.01-7.98 (m, 1H), 7.58-7.53 (m,2H), 7.46-7.29 (m, 3H), 5.35 (m, 1H), 3.80 (s, 2H), 1.30 (d, J=6.3 Hz,6H). [M+H]=355.21.

Example 425-{[6-(Difluoromethoxy)-5-[3-(propan-2-yloxy)phenyl]pyridin-3-yl]methyl}pyrimidin-2-amine

¹H NMR (400 MHz, CD₃OD) δ 8.19 (s, 2H), 8.06 (d, J=2.3 Hz, 1H),7.78-7.29 (m, 3H), 7.06-7.00 (m, 2H), 6.95-6.90 (m, 1H), 4.68-4.55 (m,1H), 3.86 (s, 2H), 1.32 (d, J=6.3 Hz, 6H). [M+H]=387.25.

Example 435-{[6-(Difluoromethoxy)-5-[3-(oxetan-3-yloxy)phenyl]pyridin-3-yl]methyl}pyrimidin-2-amine

¹H NMR (400 MHz, CD₃OD) δ 8.10 (s, 2H), 7.99 (d, J=2.3 Hz, 1H),7.69-7.24 (m, 3H), 7.04-6.99 (m, 1H), 6.84-6.80 (m, 1H), 6.75-6.70 (m,1H), 5.21 (m, 1H), 4.92 (t, J=7.0 Hz, 2H), 4.64-4.59 (m, 2H), 3.78 (s,2H). [M+H]=401.22.

Example 44N-(5-[{5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)acetamide

Step 1: To a solution of5-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine(Example 25, 50.0 mg, 0.15 mmol), in DCM (10 mL), was added anddiisopropylethylamine (40 mg, 0.31 mmol). The solution was cooled to 0°C. and acetyl chloride (230 μL, (0.23 mmol) was added dropwise. Thereaction mixture was allowed warm up to room temperature overnight, thenconcentrated to afford the corresponding imide (bis-acylated adduct),which was used crude in the next step.

Step 2:N-(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)acetamide.A solution of the crude product from step 1 in added ammonia (7N inmethanol) was stirred at room temperature for 1 h. Purification (FCC,SiO₂, 0-100% EtOAc/hexanes) afforded the title compound (11.4 mg, 21%)as an off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.44 (s, 1H), 8.59(s, 2H), 8.14 (d, J=2.7 Hz, 1H), 7.74 (d, J=2.3 Hz, 1H), 7.61-7.54 (m,1H), 7.51-7.38 (m, 3H), 3.90 (s, 2H), 3.85 (s, 3H), 2.12 (s, 3H).[M+H]=369.20.

Example 453-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(4-methanesulfonylphenyl)methyl]pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.13 (s, 1H), 7.89 (d, J=8.2 Hz, 2H),7.78-7.37 (m, 8H), 4.16 (s, 2H), 3.08 (s, 3H). [M+H]=424.16.

Example 465-{[6-(Difluoromethoxy)-5-(2-methoxypyridin-4-yl)pyridin-3-yl]methyl}pyrimidin-2-amine

¹H NMR (400 MHz, CD₃OD) δ 8.27-8.16 (m, 4H), 7.85 (d, J=2.3 Hz, 1H),7.63 (t, J=1.0 Hz, 1H), 7.16-6.96 (m, 2H), 3.96 (s, 3H), 3.89 (s, 2H).[M+H]=360.23.

Example 475-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)pyrimidin-2-amine

¹H NMR (400 MHz, CD₃OD) δ 8.23-8.20 (m, 1H), 8.18 (s, 2H), 8.11 (d,J=2.3 Hz, 1H), 7.71 (d, J=2.3 Hz, 1H), 7.56 (s, 1H), 7.41-7.36 (m, 1H),7.20-7.16 (m, 1H), 3.96 (s, 3H), 3.84 (s, 2H). [M+H]=360.23.

Example 482-[5-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)pyrimidin-2-yl]propan-2-ol

¹H NMR (400 MHz, CD₃OD) δ 8.69 (s, 2H), 8.09 (d, J=2.3 Hz, 1H), 7.63 (d,J=2.3 Hz, 1H), 7.46-7.35 (m, 2H), 7.31 (t, J=1.8 Hz, 1H), 7.12 (td,J=1.0, 7.4 Hz, 1H), 7.03-6.64 (m, 1H), 4.04 (s, 2H), 3.94 (s, 3H), 1.20(s, 6H). [M+H]=402.26.

Example 493-(3-Chlorophenyl)-2-methoxy-{[6-(trifluoromethyl)pyridin-3-yl]methyl}pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.66 (d, J=2.0 Hz, 1H), 8.08 (d, J=2.3 Hz,1H), 7.93-7.89 (m, 1H), 7.75 (d, J=8.6 Hz, 1H), 7.62 (d, J=2.3 Hz, 1H),7.55 (t, J=1.6 Hz, 1H), 7.45-7.32 (m, 3H), 4.13 (s, 2H), 3.94 (s, 3H).[M+H]=379.15.

Example 503-(3-Chlorophenyl)-2-(difluoromethoxy)-5-{[6-(propan-2-yloxy)pyridin-3-yl]methyl}pyridine

¹H NMR (400 MHz, CDCl₃) δ 8.03 (dd, J=2.15, 10.37 Hz, 2H), 7.31-7.72 (m,7H), 6.64 (d, J=8.61 Hz, 1H), 5.27 (m, 1H), 3.90 (s, 2H), 1.34 (d,J=6.26 Hz, 6H). [M+H]=405.22.

Example 513-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(6-propoxypyridin-3-yl)methyl]pyridine

¹H NMR (400 MHz, CDCl₃) δ 8.06-8.00 (m, 2H), 7.71-7.31 (m, 7H), 6.70 (d,J=9.00 Hz, 1H), 4.23 (t, J=6.85 Hz, 2H), 3.91 (s, 2H), 1.80 (q, J=6.65Hz, 2H), 1.02 (t, J=7.43 Hz, 3H).

Example 525-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1-methyl-1,2-dihydropyridin-2-one

¹H NMR (400 MHz, CD₃OD) δ 8.03 (d, J=2.0 Hz, 1H), 7.60-7.51 (m, 3H),7.47-7.30 (m, 4H), 6.51 (d, J=9.4 Hz, 1H), 3.93 (s, 3H), 3.76 (s, 2H),3.55 (s, 3H). [M+H]=341.19.

Example 53 3-(3-Chlorophenyl)-2-methoxy-5-(pyridin-4-ylmethyl)pyridine

¹H NMR (400 MHz, DMSO-d₆) δ 8.44 (d, J=4.70 Hz, 1H), 8.12 (s, 1H), 7.71(s, 1H), 7.61-7.56 (m, 2H), 7.55-7.31 (m, 3H), 7.29 (d, J=4.70 Hz, 2H),3.96 (s, 2H), 3.85 (s, 3H). [M+H]=311.13.

Example 545-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridine-2-carboxylicacid

Example 54 was prepared in a manner analogous to Example 21, with theappropriate starting materials and reagent substitutions. ¹H NMR (400MHz, DMSO-d₆) δ 8.61 (br s, 1H), 8.19 (br s, 1H), 8.12-7.94 (m, 1H),7.93-7.75 (m, 2H), 7.72-7.57 (m, 3H), 7.56-7.39 (m, 3H), 4.10 (br. s.,2H). [M+H]=391.25.

Example 553-(3-Chlorophenyl)-2-methoxy-5-[(2-methoxypyrimidin-5-yl)methyl]pyrazine

¹H NMR (400 MHz, DMSO-d₆) δ 8.58 (s, 2H), 8.23 (s, 1H), 8.03-7.86 (m,2H), 7.50 (d, J=4.30 Hz, 2H), 4.09 (s, 2H), 3.96 (s, 3H), 3.85 (s, 3H).[M+H]=343.01.

Example 565-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-N-methylpyrimidin-2-amine

¹H NMR (400 MHz, CD₃OD) δ 8.48 (br s, 1H), 8.13 (s, 2H), 8.07-7.90 (m,2H), 7.42 (d, J=5.09 Hz, 2H), 4.11-3.94 (m, 5H), 2.96 (s, 3H).[M+H]=342.05.

Example 575-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-N-cyclopropylpyrimidin-2-amine

¹H NMR (400 MHz, CD₃OD) δ 8.12-8.18 (m, 1H), 7.93-8.05 (m, 2H),7.59-7.70 (m, 1H), 7.50-7.55 (m, 1H), 7.41 (d, J=5.09 Hz, 2H), 4.09 (s,2H), 4.03 (s, 3H), 2.68 (m, 1H), 0.84-0.97 (m, 2H), 0.61-0.71 (m, 2H).[M+H]=368.06.

Example 583-(3-Chlorophenyl)-2-methoxy-5-[(1-methyl-1H-pyrazol-4-yl)methyl]pyrazine

¹H NMR (400 MHz, CD₃OD) δ 8.10-7.92 (m, 3H), 7.55 (br s, 1H), 7.45-7.39(m, 3H), 4.01 (s, 3H), 3.98 (s, 2H), 3.83 (s, 3H). [M+H]=315.01.

Example 59(4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)methanamine

¹H NMR (400 MHz, CD₃OD) δ 7.99 (d, J=1.96 Hz, 2H), 7.47 (s, 2H),7.44-7.14 (m, 6H), 3.94 (s, 2H), 3.91 (s, 3H). [M+H]=339.10.

Example 604-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridin-2-amine

¹H NMR (400 MHz, CD₃OD) δ 8.02 (d, J=1.96 Hz, 1H), 7.81-7.74 (m, 1H),7.58-7.48 (m, 2H), 7.45-7.25 (m, 3H), 6.50 (d, J=5.48 Hz, 1H), 6.43 (s,1H), 3.93 (s, 3H), 3.85 (s, 2H). [M+H]=326.01.

Example 613-(3-Chlorophenyl)-5-[(2,6-dimethylpyridin-4-yl)methyl]-2-methoxypyridine

¹H NMR (400 MHz, CD₃OD) δ 8.02 (d, J=2.35 Hz, 1H), 7.59-7.48 (m, 2H),7.47-7.25 (m, 3H), 6.97 (s, 2H), 3.98-3.86 (m, 5H), 2.43 (s, 6H).[M+H]=339.05.

Example 624-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridine-2-carbonitrile

¹H NMR (400 MHz, CD₃OD) δ 8.57 (d, J=5.09 Hz, 1H), 8.07 (d, J=2.35 Hz,1H), 7.79 (s, 1H), 7.60 (d, J=2.35 Hz, 1H), 7.54 (d, J=1.96 Hz, 2H),7.48-7.26 (m, 3H), 4.08 (s, 2H), 3.93 (s, 3H). [M+H]=336.14.

Example 634-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridine-2-carboxamide

The title compound was made in a manner analogous to Example 23, from4-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridine-2-carbonitrile(Example 62), reaction run at room temperature. ¹H NMR (400 MHz,DMSO-d₆) δ 8.49 (d, J=5.09 Hz, 1H), 8.15 (d, J=1.96 Hz, 1H), 8.05 (br s,1H), 7.92 (s, 1H), 7.74 (d, J=1.96 Hz, 1H), 7.58 (d, J=1.57 Hz, 2H),7.54-7.33 (m, 4H), 4.05 (s, 2H), 3.85 (s, 3H). [M+H]=354.15.

Example 64 3-(3-Chlorophenyl)-2-methoxy-5-(pyridin-3-ylmethyl)pyridine

¹H NMR (400 MHz, DMSO-d₆) δ 8.55 (d, J=2.0 Hz, 1H), 8.39 (dd, J=1.2, 4.7Hz, 1H), 8.13 (d, J=2.0 Hz, 1H), 7.72 (d, J=2.3 Hz, 1H), 7.70-7.66 (m,1H), 7.58 (d, J=1.6 Hz, 1H), 7.52-7.37 (m, 3H), 7.29 (dd, J=4.7, 7.8 Hz,1H), 3.96 (s, 2H), 3.85 (s, 3H). [M+H]=318.09.

Example 653-(3-Chlorophenyl)-2-methoxy-5-(1,3-thiazol-5-ylmethyl)pyridine

¹H NMR (400 MHz, DMSO-d₆) δ 8.93 (s, 1H), 8.07-8.15 (m, 1H), 7.75 (s,1H), 7.71 (d, J=2.35 Hz, 1H), 7.56-7.62 (m, 1H), 7.37-7.52 (m, 3H), 4.21(s, 2H), 3.86 (s, 3H). [M+H]=318.15.

Example 663-(3-Chlorophenyl)-5-[(dimethyl-1,3-thiazol-5-yl)methyl]-2-methoxypyridine

¹H NMR (400 MHz, DMSO-d₆) δ 8.06 (s, 1H), 7.63 (s, 1H), 7.57 (s, 1H),7.50-7.40 (m, 3H), 4.03 (s, 2H), 3.85 (s, 3H), 2.48 (s, 3H), 2.28 (s,3H). [M+H]=345.17.

Example 673-(3-Chlorophenyl)-2-methoxy-5-[(6-methoxy-5-methylpyridin-3-yl)methyl]pyridine

¹H NMR (400 MHz, DMSO-d₆) δ 8.09 (d, J=2.3 Hz, 1H), 7.99 (d, J=2.3 Hz,1H), 7.94 (d, J=2.0 Hz, 1H), 7.69-7.62 (m, 1H), 7.59-7.52 (m, 1H),7.51-7.36 (m, 3H), 3.87-3.84 (m, 6H), 3.82 (s, 2H), 3.81 (s, 3H).[M+H]=356.09.

Example 683-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1,3-thiazol-5-ylmethyl)pyridine

¹H NMR (400 MHz, DMSO-d₆) δ 8.94 (s, 1H), 8.22 (d, J=2.0 Hz, 1H), 7.94(d, J=2.3 Hz, 1H), 7.77 (s, 1H), 7.69 (s, 1H), 7.59 (s, 1H), 7.53-7.45(m, 3H), 4.29 (s, 2H). [M+H]=354.12.

Example 693-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(dimethyl-1,3-thiazol-5-yl)methyl]pyridine

¹H NMR (400 MHz, DMSO-d₆) δ 8.14 (d, J=2.0 Hz, 1H), 7.88-7.83 (m, 1H),7.68 (s, 1H), 7.62-7.57 (m, 1H), 7.55-7.45 (m, 3H), 4.11 (s, 2H), 2.51(s, 3H), 2.29 (s, 3H). [M+H]=381.15.

Example 705-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridine-3-carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ 8.86 (d, J=2.0 Hz, 1H), 8.70 (d, J=2.0 Hz,1H), 8.26 (d, J=2.0 Hz, 1H), 8.10 (s, 2H), 7.98 (d, J=2.3 Hz, 1H), 7.60(s, 1H), 7.55 (br s, 1H), 7.52-7.43 (m, 4H), 4.09 (s, 2H). [M+H]=391.05.

Example 71(5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridin-3-yl)methanamine

Step 1. tert-Butyl((5-((5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)methyl)pyridin-3-yl)methyl)carbamate.The title compound was prepared in a manner analogous to Example 1, withthe appropriate starting material substitutions.

Step 2.(5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridin-3-yl)methanamine.Purified compound from step 1, was treated with a solution of 20%trifluoroacetic acid in DCM and stirred at room temperature for 4 h. Thesolvent was removed under reduced pressure and the residue partitionedbetween EtOAc and saturated sodium bicarbonate. The organic layers werewashed with brine, dried (Na₂SO₄) and concentrated under reducedpressure to afford the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ8.61-8.47 (m, 1H), 8.31 (m, 2H), 8.22 (br s, 1H), 7.97-7.80 (m, 2H),7.72-7.57 (m, 2H), 7.50 (br s, 2H), 4.12-4.03 (m, 2H), 4.00 (s, 2H),3.15 (d, J=4.7 Hz, 2H). [M+H]=377.25.

Example 723-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(6-methylpyridin-3-yl)methyl]pyridine

¹H NMR (400 MHz, DMSO-d₆) δ 8.42 (s, 1H), 8.20 (d, J=2.0 Hz, 1H), 7.91(d, J=2.0 Hz, 1H), 7.85 (s, 1H), 7.89-7.83 (m, 1H), 7.69-7.65 (m, 1H),7.67 (s, 1H), 7.61-7.54 (m, 3H), 3.97 (s, 2H), 2.39 (s, 3H).[M+H]=361.06.

Example 733-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(2-methyl-1,3-thiazol-5-yl)methyl]pyridine

¹H NMR (400 MHz, DMSO-d₆) δ 8.20 (s, 1H), 7.94-7.84 (m, 1H), 7.69 (s,1H), 7.59 (s, 1H), 7.53-7.42 (m, 4H), 4.19 (s, 2H), 2.55 (s, 3H).[M+H]=368.02.

Example 743-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1,3-thiazol-2-ylmethyl)pyridine

¹H NMR (400 MHz, DMSO-d₆) δ 8.27 (s, 1H), 8.01 (s, 1H), 7.74-7.64 (m,1H), 7.63-7.56 (m, 2H), 7.55-7.41 (m, 4H), 4.43 (s, 2H). [M+H]=354.05.

Example 755-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-2-methylpyrimidine

¹H NMR (400 MHz, DMSO-d₆) δ 8.55 (s, 2H), 8.13 (d, J=2.3 Hz, 1H), 7.72(d, J=2.3 Hz, 1H), 7.63-7.56 (m, 1H), 7.53-7.34 (m, 3H), 4.02 (s, 2H),3.80 (s, 3H), 3.85 (s, 3H). [M+H]=327.15.

Example 765-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-2-methoxypyrimidine

¹H NMR (400 MHz, DMSO-d₆) δ 8.55 (s, 2H), 8.13 (d, J=2.3 Hz, 1H), 7.72(d, J=2.3 Hz, 1H), 7.63-7.56 (m, 1H), 7.53-7.34 (m, 3H), 4.02 (s, 2H),3.80 (s, 3H), 3.85 (s, 3H). [M+H]=342.15.

Example 775-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N-(propan-2-yl)pyrimidin-2-amine

¹H NMR (400 MHz, DMSO-d₆) δ 8.30 (s, 2H), 8.11 (d, J=2.3 Hz, 1H), 7.70(d, J=2.3 Hz, 1H), 7.58 (t, J=1.8 Hz, 1H), 7.53-7.36 (m, 3H), 7.35 (brs, 1H), 4.03-3.89 (m, 1H), 3.85 (s, 3H), 3.75 (s, 2H), 1.11 (d, J=6.3Hz, 6H). [M+H]=370.05.

Example 785-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine

¹H NMR (400 MHz, DMSO-d₆) δ 9.02 (s, 1H), 8.77 (s, 2H), 8.16 (d, J=2.3Hz, 1H), 7.76 (d, J=2.3 Hz, 1H), 7.65-7.36 (m, 4H), 3.98 (s, 2H), 3.30(s, 3H). [M+H]=313.01.

Example 793-(3-Chlorophenyl)-2-methoxy-5-[(1-methyl-1H-pyrazol-4-yl)methyl]pyridine

¹H NMR (400 MHz, DMSO-d₆) δ 8.05 (d, J=2.0 Hz, 1H), 7.61 (d, J=2.3 Hz,1H), 7.57 (s, 1H), 7.52-7.38 (m, 4H), 7.28 (s, 1H), 3.84 (s, 3H), 3.75(s, 2H), 3.65 (s, 3H). [M+H]=315.02.

Example 803-(3-Chlorophenyl)-2-methoxy-5-(1H-pyrazol-4-ylmethyl)pyridine

Step 1. tert-Butyl4-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)-1H-pyrazole-1-carboxylate.The title compound was prepared in a manner analogous to Example 1, withthe appropriate starting material substitutions.

Step 2. Purified compound from Step 1, was treated with a solution of20% trifluoroacetic acid in DCM and stirred at room temperature for 4 h.The solvent was removed under reduced pressure and the residuepartitioned between EtOAc and saturated sodium bicarbonate. The organiclayers were washed with brine, dried (Na₂SO₄), and concentrated underreduced pressure to afford the title compound. ¹H NMR (400 MHz, DMSO-d₆)δ 8.05 (d, J=2.0 Hz, 1H), 7.62 (d, J=2.0 Hz, 1H), 7.58-7.54 (m, 3H),7.50-7.36 (m, 4H), 3.84 (s, 3H), 3.72 (s, 2H). [M+H]=301.02.

Example 815-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N-methylpyrimidin-2-amine

¹H NMR (400 MHz, DMSO-d₆) δ 8.34 (s, 2H), 8.11 (d, J=2.0 Hz, 1H), 7.84(br s, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.58 (t, J=1.8 Hz, 1H), 7.53-7.36(m, 3H), 3.83 (s 3H), 3.80-3.75 (m, 3H), 3.73 (s, 2H). [M+H]=342.05.

Example 825-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N-cyclopropylpyrimidin-2-amine

¹H NMR (400 MHz, DMSO-d₆) δ 8.34 (s, 2H), 8.11 (d, J=2.0 Hz, 1H), 7.84(br s, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.58 (t, J=1.8 Hz, 1H), 7.53-7.36(m, 3H), 3.80 (s, 3H), 3.78 (s, 2H), 2.68-2.56 (m, 1H), 0.71-0.61 (m,2H), 0.53-0.38 (m, 2H). [M+H]=368.02.

Example 835-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N,N-dimethylpyrimidin-2-amine

¹H NMR (400 MHz, DMSO-d₆) δ 8.38 (s, 2H), 8.16 (d, J=2.0 Hz, 1H), 7.72(d, J=2.0 Hz, 1H), 7.56 (t, J=1.8 Hz, 1H), 7.50-7.36 (m, 3H), 3.86 (s3H), 3.73 (s, 2H), 3.01 (s, 6H). [M+H]=355.18.

Example 845-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N-(2,2,2-trifluoroethyl)pyrimidin-2-amine

¹H NMR (400 MHz, DMSO-d₆) δ 8.38 (s, 2H), 8.16 (d, J=2.0 Hz, 1H), 7.84(br s, 1H), 7.72 (d, J=2.0 Hz, 1H), 7.56 (t, J=1.8 Hz, 1H), 7.50-7.36(m, 3H), 4.10-4.01 (m, 2H), 3.86 (s 3H), 3.73 (s, 2H). [M+H]=409.14.

Example 85 Methyl4-{[6-(3-chlorophenyl)-5-methoxypyrazin-2-yl]methyl}benzoate

[M+H]=369.16

Example 864-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}benzonitrile

[M+H]=336.6

Example 875-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}pyrimidin-2-amine

¹H NMR (400 MHz, CD₃OD) δ 8.29 (s, 1H), 8.09 (s, 1H), 8.04 (s, 1H), 7.98(t, J=3.72 Hz, 1H), 7.69-7.52 (m, 1H), 7.41 (d, J=5.09 Hz, 2H), 4.03 (s,3H), 3.98 (s, 2H). [M+H]=328.21.

Example 883-(3-Chlorophenyl)-5-[(4-fluorophenyl)methyl]-2-methoxypyridine

¹H NMR (400 MHz, CD₃OD) δ 7.99 (d, J=2.3 Hz, 1H), 7.51 (t, J=2.5 Hz,2H), 7.42-7.21 (m, 5H), 7.01 (t, J=8.8 Hz, 2H), 3.95 (s, 2H), 3.92 (s,3H). [M+H]=328.26.

Example 895-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyrimidin-2-amine

¹H NMR (400 MHz, CD₃OD) δ 8.11 (s, 2H), 8.01 (d, J=2.3 Hz, 1H),7.70-7.63 (m, 1H), 7.50 (s, 1H), 7.45 (s, 1H), 7.38-7.28 (m, 3H), 3.78(s, 2H). [M+H]=363.30.

Example 905-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}pyridine-2-carboxamide

Step 1. Methyl5-((6-(3-chlorophenyl)-5-methoxypyrazin-2-yl)methyl)picolinate. Preparedin a manner analogous to Example 1 from(6-(methoxycarbonyl)pyridin-3-yl)boronic acid and Intermediate 3, toaffords 20 mg of the corresponding methyl ester as an orange oil.[M+H]=370.10.

Step 2.5-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}pyridine-2-carboxamide.A solution of5-((6-(3-chlorophenyl)-5-methoxypyrazin-2-yl)methyl)picolinate (fromStep 1) and ammonia (7N in methanol) was heated at 60° C. for 8 h, thenconcentrated under reduced pressure. Trituration with diethyl etherobtained the title compound (12 mg, 70%) as a yellow solid. ¹H NMR (400MHz, CD₃OD) δ 8.66 (br s, 1H), 8.14 (s, 1H), 8.07 (d, J=7.83 Hz, 1H),8.02 (s, 1H), 7.69-7.60 (m, 1H), 7.59-7.50 (m, 1H), 7.41 (d, J=4.70 Hz,2H), 4.27 (s, 2H), 4.00-4.09 (m, 3H). [M+H]=355.10.

Example 915-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-N-cyclopropylpyrimidin-2-amine

¹H NMR (400 MHz, CD₃OD) δ 8.25 (br s, 2H), 8.11 (br s, 1H), 7.75 (br s,1H), 7.48-7.68 (m, 2H), 7.35-7.46 (m, 3H), 3.90 (br s, 2H), 2.63 (br s,1H), 0.76 (d, J=6.26 Hz, 2H), 0.51 (br s, 2H). [M+H]=403.12.

Example 925-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-2-methoxypyrimidine

¹H NMR (400 MHz, CD₃OD) δ 8.49 (br s, 2H), 8.13 (br s, 1H), 7.78 (d,J=2.74 Hz, 1H), 7.63-7.49 (m, 2H), 7.47-7.31 (m, 3H), 4.07-3.81 (m, 5H).[M+H]=376.20.

Example 935-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-N-methylpyrimidin-2-amine

¹H NMR (400 MHz, CD₃OD) δ 8.20 (br s, 2H), 8.10 (br s, 1H), 7.74 (br s,2H), 7.68-7.49 (m, 1H), 7.46-7.27 (m, 3H), 3.87 (br s, 2H), 2.89 (br s,3H). [M+H]=377.10.

Example 945-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-N-(2,2,2-trifluoroethyl)pyrimidin-2-amine

¹H NMR (400 MHz, CD₃OD) δ 8.27 (br s, 2H), 8.10 (br s, 1H), 7.80-7.68(m, 1H), 7.61-7.49 (m, 1H), 7.47-7.31 (m, 4H), 4.19-4.02 (m, 2H), 3.90(br s, 2H). [M+H]=445.10.

Example 953-(3-Chlorophenyl)-2-methoxy-5-(1,2-oxazol-4-ylmethyl)pyrazine

¹H NMR (400 MHz, CD₃OD) δ 8.58 (s, 1H), 8.09 (s, 1H), 8.43 (s, 1H), 8.05(s, 1H), 8.02-7.95 (m, 1H), 7.47-7.38 (m, 2H), 4.20-3.90 (m, 5H).[M+H]=302.10.

Example 963-(3-Chlorophenyl)-2-methoxy-5-(1,2-oxazol-4-ylmethyl)pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.52 (s, 1H), 8.34 (s, 1H), 8.04 (s, 1H),7.60-7.53 (m, 2H), 7.46-7.27 (m, 3H), 3.93 (s, 3H), 3.85 (s, 2H).[M+H]=301.10.

Example 973-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1,2-oxazol-4-ylmethyl)pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.55 (s, 1H), 8.36 (s, 1H), 8.12 (d, J=1.96Hz, 1H), 7.77 (s, 1H), 7.59 (s, 1H), 7.55 (s, 1H), 7.48-7.31 (m, 3H),3.91 (s, 2H). [M+H]=337.10.

Example 983-(3-Chlorophenyl)-5-[(dimethyl-1,2-oxazol-4-yl)methyl]-2-methoxypyrazine

¹H NMR (400 MHz, CD₃OD) δ 8.07-7.88 (m, 2H), 7.46-7.30 (m, 3H), 4.03 (s,3H), 3.89 (br s, 2H), 2.40 (br s, 3H), 2.21 (s, 3H). [M+H]=330.79.

Example 993-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(dimethyl-1,2-oxazol-4-yl)methyl]pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.01 (br s, 1H), 7.64 (br s, 1H), 7.58 (br s,1H), 7.53 (br s, 1H), 7.47-7.31 (m, 3H), 3.81 (br s, 2H), 2.36 (br s,3H), 2.12 (br s, 3H). [M+H]=365.20.

Example 100 Methyl2-(4-{[5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}phenyl)acetate

¹H NMR (400 MHz, CD₃OD) δ 8.08 (d, J=2.35 Hz, 1H), 8.02 (d, J=2.35 Hz,1H), 7.76 (s, 1H), 7.71-7.66 (m, 1H), 7.56-7.59 (m, 1H), 7.55 (s, 1H),7.57-7.46 (m, 1H), 7.45-7.36 (m, 4H), 4.01 (s, 2H), 3.67 (s, 3H), 3.61(s, 2H). [M+H]=418.29.

Example 101 Ethyl1-(4-{[5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}phenyl)cyclopropane-1-carboxylate

¹H NMR (400 MHz, CD₃OD) δ 8.08 (d, J=2.35 Hz, 1H), 7.76 (s, 1H), 7.68(d, J=2.35 Hz, 1H), 7.59-7.52 (m, 1H), 7.52-7.47 (m, 2H), 7.45-7.36 (m,4H), 7.31-7.27 (m, 1H), 4.10-4.05 (m, 4H), 4.03 (m, 1H), 4.00 (s, 2H),1.55-1.49 (m, 2H), 1.14-1.19 (m, 3H). [M+H]=445.10.

Example 1023-(3-Chlorophenyl)-5-{[6-(cyclopropylmethoxy)pyridin-3-yl]methyl}-2-(difluoromethoxy)pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.08-8.05 (m, 1H), 8.01-7.90 (m, 1H), 7.71 (d,J=2.35 Hz, 1H), 7.58 (s, 1H), 7.50-7.45 (m, 1H), 7.43-7.36 (m, 4H),6.75-6.73 (m, 1H), 4.05 (d, J=7.04 Hz, 2H), 3.96 (s, 2H), 1.32-1.17 (m,1H), 0.52-0.63 (m, 2H), 0.25-0.36 (m, 2H). [M+H]=417.33.

Example 1035-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyridine-2-carbonitrile

¹H NMR (400 MHz, CD₃OD) δ 8.73 (d, J=1.6 Hz, 1H), 8.13 (s, 1H),8.01-7.90 (m, 2H), 7.86 (t, J=1.8 Hz, 1H), 7.80 (dd, J=0.8, 7.8 Hz, 1H),7.46 (t, J=8.0 Hz, 1H), 7.19 (dd, J=2.0, 8.2 Hz, 1H), 7.05-6.59 (m, 1H),4.48 (q, J=7.3 Hz, 2H), 4.27 (s, 2H), 1.43 (t, J=7.0 Hz, 3H).[M+H]=383.26.

Example 1045-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyrimidin-2-amine

¹H NMR (400 MHz, CD₃OD) δ 8.52 (s, 2H), 8.13 (s, 1H), 7.95 (qd, J=0.9,7.9 Hz, 1H), 7.89-7.85 (m, 1H), 7.47 (t, J=8.2 Hz, 1H), 7.20 (dd, J=3.3,8.0 Hz, 1H), 7.05-6.62 (m, 1H), 4.49 (q, J=7.2 Hz, 2H), 4.07 (s, 2H),1.43 (t, J=7.0 Hz, 3H). [M+H]=374.14.

Example 1055-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}pyrimidin-2-amine

¹H NMR (400 MHz, DMSO-d₆) δ 8.23-8.17 (m, 2H), 8.15 (s, 1H), 8.05-8.02(m, 1H), 7.99 (ddd, J=1.6, 3.6, 5.4 Hz, 1H), 7.52-7.47 (m, 2H), 6.44 (s,2H), 4.41 (q, J=7.0 Hz, 2H), 3.90 (s, 2H), 1.35 (t, J=7.0 Hz, 3H).[M+H]=342.15.

Example 1065-({6-[3-(Difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)pyrimidin-2-amine

¹H NMR (400 MHz, DMSO-d₆) δ 8.23-8.14 (m, 3H), 7.88 (d, J=8.2 Hz, 1H),7.77 (s, 1H), 7.52 (t, J=8.0 Hz, 1H), 7.29-7.21 (m, 1H), 7.09-5.70 (m,3H), 3.95 (s, 3H), 3.90 (s, 2H). [M+H]=360.21.

Example 1075-({6-[3-(Difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)pyrimidine-2-carbonitrile

¹H NMR (400 MHz, CD₃OD) δ 8.94 (s, 2H), 8.19 (s, 1H), 7.90 (td, J=1.4,7.8 Hz, 1H), 7.79 (t, J=2.2 Hz, 1H), 7.46 (t, J=8.0 Hz, 1H), 7.19 (dd,J=2.3, 8.2 Hz, 1H), 7.03-6.62 (m, 1H), 4.28 (s, 2H), 4.04 (s, 3H).M+H]=370.19.

Example 1085-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}pyrimidine-2-carbonitrile

¹H NMR (400 MHz, CD₃OD) δ 8.93 (s, 2H), 8.17 (s, 1H), 8.06-8.02 (m, 1H),7.97 (ddd, J=1.6, 3.7, 5.3 Hz, 1H), 7.43-7.38 (m, 2H), 4.49 (q, J=7.0Hz, 2H), 4.27 (s, 2H), 1.43 (t, J=7.0 Hz, 3H). [M+H]=352.26.

Example 1093-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(pyridin-2-ylmethyl)pyridine

Step 1.((5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)methyl)zinc(II)bromide. To a suspension of zinc (42.77 mg, 0.65 mmol) in THF (1 mL) wasadded 1,2-dibromoethane (2.48 μL, 0.03 mmol). The resulting mixture washeated at 70° C. for 10 minutes before being cooled to room temperature.Once cooled, trimethylsilylchloride (2.92 μL, 0.02 mmol) was added andthe solution was stirred at room temperature for an additional 30 min.To the activated zinc solution was added5-(bromomethyl)-3-(3-chlorophenyl)-2-(difluoromethoxy)pyridine(Intermediate 12, 200 mg, 0.57 mmol) and the resulting mixture washeated at 70° C. for 8 h. The reaction mixture was cooled to roomtemperature and decanted from the solids to afford a −0.5 M solution ofthe title compound.

Step 2.3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(pyridin-2-ylmethyl)pyridine.To a solution of 2-bromopyridine (29.89 μL, 0.31 mmol) andtetrakis(triphenylphosphine)palladium(0) (9.88 mg, 0.01 mmol) in THF(3.00 mL) was added((5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)methyl)zinc(II)bromide (500.00 μL, 0.57 mol/L, 0.29 mmol, from step 1). The resultingsolution was heated at 70° C. for 5 h. The solvent was removed, and thecrude material was purified on the Shimadzu HPLC using the 5-95%gradient with TFA to obtain the title compound TFA salt as an oil (21mg, 16%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.72-8.78 (m, 1H), 8.46 (dt,J=1.57, 8.02 Hz, 1H), 8.23 (d, J=2.35 Hz, 1H), 7.84-7.93 (m, 3H),7.39-7.83 (m, 5H), 4.50 (s, 2H). [M+H]=347.08.

Examples 110-111 were prepared in a manner analogous to Example 109,with the appropriate starting materials and reagent substitutions.

Example 1102-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyrazine

¹H NMR (400 MHz, CD₃OD) δ 8.65 (d, J=1.57 Hz, 1H), 8.55 (dd, J=1.57,2.74 Hz, 1H), 8.47 (d, J=2.74 Hz, 1H), 8.18 (d, J=2.35 Hz, 1H), 7.86 (d,J=2.35 Hz, 1H), 7.79-7.36 (m, 5H), 4.25 (s, 2H). [M+H]=348.06.

Example 1116-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridazin-3-amine

¹H NMR (400 MHz, CD₃OD) δ 8.18 (d, J=2.35 Hz, 1H), 7.84 (d, J=2.35 Hz,1H), 7.79 (d, J=2.35 Hz, 1H), 7.39-7.78 (m, 6H), 4.19 (s, 2H).[M+H]=363.16.

Example 1123-(3-Chlorophenyl)-2-methoxy-6-methyl-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine

To a solution of3-(chloromethyl)-5-(3-chlorophenyl)-6-methoxy-2-methylpyridine(Intermediate 8, 87 mg, 0.31 mmol), in acetone (12 mL), was added1H-1,2,4-triazole (32 mg, 0.46 mmol), and cesium carbonate (150 mg, 0.63mmol). The reaction mixture stirred at room temperature for 2 h, thenfiltered and concentrated under reduced pressure. Purification (FCC,SiO₂, 0-100%, EtOAc/hexanes) afforded the title compound (82.4 mg, 84%).¹H NMR (400 MHz, CDCl₃) δ 8.03 (s, 1H), 7.98 (s, 1H), 7.52 (s, 1H),7.45-7.37 (m, 2H), 7.37-7.29 (m, 2H), 5.34 (s, 2H), 3.98 (s, 3H), 2.52(s, 3H). [M+H]=315.22.

Examples 113, 115, 117, 123, 125-126 were prepared in a manner analogousto Example 13, with the appropriate starting materials and reagentsubstitutions.

Example 1134-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}benzamide

¹H NMR (400 MHz, CD₃OD) δ 8.02-8.08 (m, 2H), 7.98 (td, J=4.30, 1.57 Hz,1H), 7.81 (d, J=8.22 Hz, 2H), 7.47-7.37 (m, 4H), 4.21 (s, 2H), 4.02 (s,3H). [M+H]=354.20.

Example 1145-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridine-2-carboxamide

The title compound was prepared in a manner analogous to Example 90,with the appropriate starting material substitutions. ¹H NMR (400 MHz,CD₃OD) δ 8.49 (d, J=2.0 Hz, 1H), 8.05 (d, J=2.3 Hz, 1H), 7.95 (d, J=8.2Hz, 1H), 7.75 (dd, J=2.0, 8.2 Hz, 1H), 7.71-7.27 (m, 6H), 4.07 (s, 2H).[M+H]=390.16.

Example 1155-{[6-(Difluoromethoxy)-5-(3-methoxyphenyl)pyridin-3-yl]methyl}pyrimidine-2-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.85 (s, 2H), 8.14 (d, J=2.35 Hz, 1H), 7.81(d, J=2.35 Hz, 1H), 7.38-7.30 (m, 1H), 7.59 (s, 1H), 7.10-7.03 (m, 2H)6.95 (dd, J=8.22, 1.57 Hz, 1H) 3.81 (s, 3H) 4.17 (s, 2H). [M+H]=387.32.

Example 1165-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridine-2-carboxamide

The title compound was prepared in a manner analogous to Example 90,with the appropriate starting material substitutions. ¹H NMR (400 MHz,CD₃OD) δ 8.56 (d, J=1.6 Hz, 1H), 8.09-8.00 (m, 2H), 7.82 (dd, J=2.0, 8.2Hz, 1H), 7.59 (d, J=2.3 Hz, 1H), 7.53 (s, 1H), 7.45-7.30 (m, 3H), 4.09(s, 2H), 3.93 (s, 3H). [M+H]=354.20.

Example 1175-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyrimidine-2-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.85 (s, 2H), 8.18 (d, J=2.3 Hz, 1H), 7.84 (d,J=2.3 Hz, 1H), 7.80-7.37 (m, 5H), 4.18 (s, 2H). [M+H]=391.16.

Example 1185-{[5-(3-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.83 (s, 2H), 8.11 (d, J=2.3 Hz, 1H), 7.65 (d,J=2.3 Hz, 1H), 7.45-7.26 (m, 3H), 7.10-7.02 (m, 1H), 4.12 (s, 2H), 3.94(s, 3H). [M+H]=339.18.

Example 1195-({5-[3-(Difluoromethoxy)phenyl]-6-ethoxypyridin-3-yl}methyl)pyrimidine-2-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.84 (s, 2H), 8.09 (d, J=2.3 Hz, 1H), 7.66 (d,J=2.3 Hz, 1H), 7.46-7.35 (m, 3H), 7.17-7.08 (m, 1H), 7.03-6.61 (m, 1H),4.40 (q, J=7.0 Hz, 2H), 4.12 (s, 2H), 1.35 (t, J=7.0 Hz, 3H).[M+H]=401.27.

Example 1205-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)pyrimidine-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ 8.91 (s, 2H), 8.33-8.27 (m, 2H), 8.12 (br s,1H), 7.95 (d, J=2.3 Hz, 1H), 7.93-7.55 (m, 2H), 7.50 (dd, J=1.6, 5.5 Hz,1H), 7.32-7.29 (m, 1H), 4.09 (s, 2H), 3.91 (s, 3H). [M+H]=388.24.

Example 1215-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)pyrimidine-2-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.84 (s, 2H), 8.11 (d, J=2.3 Hz, 1H), 7.66 (d,J=2.3 Hz, 1H), 7.46-7.35 (m, 2H), 7.32 (t, J=1.8 Hz, 1H), 7.14-7.10 (m,1H), 6.83 (t, J=1.0 Hz, 1H), 4.13 (s, 2H), 3.95 (s, 3H). [M+H]=387.25.

Example 1225-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-ethoxypyridin-3-yl}methyl)pyrimidine-2-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.84 (s, 2H), 8.23-8.15 (m, 2H), 7.79 (s, 1H),7.75-7.36 (m, 2H), 7.22-7.20 (m, 1H), 4.44 (q, J=7.0 Hz, 2H), 4.13 (s,2H), 1.37 (t, J=7.0 Hz, 3H). [M+H]=402.26.

Example 1235-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}pyrimidine-2-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.94 (s, 2H), 8.20 (s, 1H), 8.02 (s, 1H),7.99-7.91 (m, 1H), 7.41 (d, J=5.09 Hz, 2H), 4.28 (s, 2H), 4.04 (s, 3H).[M+H]=356.20.

Example 1245-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyridine-2-carboxamide

The title compound was prepared in a manner analogous to Example 90,with the appropriate starting material substitutions. ¹H NMR (400 MHz,CD₃OD) δ 8.66-8.63 (m, 1H), 8.11 (s, 1H), 8.04 (dd, J=0.8, 7.8 Hz, 1H),7.98-7.85 (m, 3H), 7.46 (t, J=8.2 Hz, 1H), 7.19 (dd, J=2.0, 8.2 Hz, 1H),7.04-6.61 (m, 1H), 4.48 (q, J=7.0 Hz, 2H), 4.25 (s, 2H), 1.43 (t, J=7.0Hz, 3H). [M+H]=401.25.

Example 1255-({6-[3-(Difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)pyrimidine-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ 8.92 (s, 2H), 8.29 (s, 1H), 8.12 (br s, 1H),7.88-7.82 (m, 1H), 7.74 (t, J=2.0 Hz, 1H), 7.71 (br s, 1H), 7.52 (t,J=8.0 Hz, 1H), 7.45-7.03 (m, 2H), 4.26 (s, 2H), 3.96 (s, 3H).[M+H]=388.15.

Example 1265-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}pyrimidine-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ 8.92 (s, 2H), 8.27 (s, 1H), 8.13 (br s, 1H),8.04-7.99 (m, 1H), 7.99-7.91 (m, 1H), 7.71 (br s, 1H), 7.52-7.45 (m,2H), 4.48-4.37 (m, 2H), 4.25 (s, 2H), 1.40-1.28 (m, 3H). [M+H]=370.05.

Example 127 Methyl1-{[6-(3-chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-1,2,4-triazole-3-carboxylate

To a solution of 5-(bromomethyl)-3-(3-chlorophenyl)-2-methoxypyrazine(Intermediate 3, 200.00 mg, 0.64 mmol), in acetone (3.19 mL), was addedmethyl 1H-1,2,4-triazole-3-carboxylate (121.60 mg, 0.96 mmol) andpotassium carbonate (264.44 mg, 1.91 mmol). The reaction was stirred atroom temperature for 2 h. The LCMS showed two peaks with [M+H] valuesconsistent with the two major regioproducts. The mixture was dilutedwith DCM (5 mL), dried (Na₂SO₄) and concentrated under reduced pressure.Purification (FCC, SiO₂, 20-100% EtOAc/hexanes) afforded the titlecompound (100 mg; 44%). 1H NMR (400 MHz, CD₃OD) δ 8.79 (s, 1H), 8.26 (s,1H), 8.01 (td, J=1.1, 2.1 Hz, 1H), 7.99-7.90 (m, 1H), 7.45-7.36 (m, 2H),5.64 (s, 2H), 4.07 (s, 3H), 3.92 (s, 3H). [M+H]=360.24.

Examples 128-149, 151-197 were prepared in a manner analogous to Example4 or Example 127 with the appropriate starting materials and reagentsubstitutions.

Example 1283-(3-Chlorophenyl)-5-[(3-cyclopropyl-1H-1,2,4-triazol-1-yl)methyl]-2-(difluoromethoxy)pyridine

¹H NMR (400 MHz, CDCl₃) δ 7.96 (s, 1H), 7.71-7.63 (m, 1H), 7.50 (d,J=19.17 Hz, 1H), 7.39 (s, 2H), 7.26 (s, 2H), 5.26 (s, 2H), 3.70 (s, 1H),2.04 (s, 1H), 1.55 (s, 1H), 0.95 (d, J=6.65 Hz, 3H). [M+H]=377.22.

Example 1293-(3-Fluorophenyl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.60 (s, 1H), 8.19 (d, J=2.7 Hz, 1H), 8.00 (s,1H), 7.75 (d, J=2.3 Hz, 1H), 7.45-7.38 (m, 1H), 7.34-7.26 (m, 2H),7.12-7.05 (m, 1H), 5.44 (s, 2H), 3.95 (s, 3H). [M+H]=285.26.

Example 1303-(3-Chlorophenyl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyrazine

¹H NMR (400 MHz, CD₃OD) δ 8.68 (s, 1H), 8.20 (s, 1H), 8.01 (s, 2H),7.98-7.92 (m, 1H), 7.44-7.39 (m, 2H), 5.58 (s, 2H), 4.06 (s, 3H).[M+H]=302.31.

Example 1313-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.63 (s, 1H), 8.25 (d, J=2.3 Hz, 1H), 8.02 (s,1H), 7.92 (d, J=2.3 Hz, 1H), 7.83-7.61 (m, 1H), 7.56 (s, 1H), 7.50-7.39(m, 3H), 5.51 (s, 2H). [M+H]=337.15.

Example 1323-(3-Chlorophenyl)-2-methoxy-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyrazine

as a mixture

¹H NMR (400 MHz, CD₃OD) δ 8.54 (s, 2H), 8.18 (d, J=6.65 Hz, 2H),7.90-8.05 (m, 4H), 7.85 (s, 2H), 7.37-7.47 (m, 4H), 5.50 (d, J=10.17 Hz,4H), 4.07 (s, 6H), 2.27-2.69 (m, 6H). [M+H]=316.22.

Example 1333-(3-Chlorophenyl)-5-[(3-cyclopropyl-1H-1,2,4-triazol-1-yl)methyl]-2-methoxypyrazine

as a mixture

¹H NMR (400 MHz, CD₃OD) δ 8.47 (s, 1H), 8.16 (s, 2H), 8.01 (d, J=1.2 Hz,4H), 7.78 (s, 1H), 7.44-7.39 (m, 4H), 5.62 (s, 2H), 5.45 (s, 2H), 4.06(m, 6H), 2.43-2.33 (m, 1H), 2.04-1.94 (m, 1H), 1.20-0.84 (m, 8H).[M+H]=342.33.

Example 1343-(3-Chlorophenyl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine

¹H NMR (400 MHz, CDCl₃) δ 8.16 (d, J=2.3 Hz, 1H), 8.12 (s, 1H), 7.98 (s,1H), 7.55 (d, J=2.3 Hz, 1H), 7.51 (d, J=0.8 Hz, 1H), 7.43-7.32 (m, 3H),5.33 (s, 2H), 3.98 (s, 3H). [M+H]=301.19.

Example 1353-(3-Chlorophenyl)-2-(propan-2-yloxy)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.63-8.57 (m, 1H), 8.16 (d, J=2.3 Hz, 1H),8.00 (s, 1H), 7.73 (d, J=2.3 Hz, 1H), 7.56 (s, 1H), 7.49-7.31 (m, 3H),5.44-5.40 (m, 3H), 1.31 (d, J=6.3 Hz, 6H). [M+H]=329.26.

Example 1363-[2-Methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridin-3-yl]benzonitrile

¹H NMR (400 MHz, DMSO-d₆) δ 8.67 (s, 1H), 8.25 (d, J=2.3 Hz, 1H), 7.99(m, 2H), 7.91-7.83 (m, 3H), 7.69-7.62 (m, 1H), 5.43 (s, 2H), 3.90 (s,3H). [M+H]=292.26.

Example 1372-Methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)-3-[3-(trifluoromethoxy)phenyl]pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.60 (s, 1H), 8.21 (d, J=2.3 Hz, 1H), 8.00 (s,1H), 7.77 (d, J=2.3 Hz, 1H), 7.54-7.45 (m, 3H), 7.27 (d, J=6.3 Hz, 1H),5.45 (s, 2H), 3.96 (s, 3H). [M+H]=351.29.

Example 1383-(3-Chlorophenyl)-2-methoxy-5-[(3-methyl-4H-1,2,4-triazol-4-yl)methyl]pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.52 (s, 1H), 8.13 (d, J=2.3 Hz, 1H), 7.66 (d,J=2.3 Hz, 1H), 7.55 (s, 1H), 7.47-7.33 (m, 3H), 5.27 (s, 2H), 3.96 (s,3H), 2.45 (s, 3H). [M+H]=315.10.

Example 1393-(3,5-Difluorophenyl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.60 (s, 1H), 8.22 (d, J=2.3 Hz, 1H), 8.00 (s,1H), 7.80 (d, J=2.3 Hz, 1H), 7.18 (dd, J=2.0, 8.6 Hz, 2H), 7.00-6.89 (m,1H), 5.44 (s, 2H), 3.97 (s, 3H). [M+H]=303.09.

Example 140 Methyl1-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazole-5-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 8.31-8.23 (m, 1H), 8.00 (s, 1H), 7.70-7.63 (m,1H), 7.52-7.45 (m, 1H), 7.41-7.29 (m, 3H), 5.79 (s, 2H), 4.05-3.92 (m,6H). [M+H]=359.33.

Example 141 Methyl1-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazole-3-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 8.21-8.18 (m, 1H), 8.18-8.15 (m, 1H), 7.56 (s,1H), 7.50 (d, J=1.2 Hz, 1H), 7.38-7.33 (m, 3H), 5.41 (s, 2H), 3.99 (m,6H). [M+H]=359.35.

Example 1423-(4-Chlorothiophen-2-yl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.58 (br s, 1H), 8.05 (d, J=2.0 Hz, 1H),8.02-7.89 (m, 2H), 7.44 (d, J=1.2 Hz, 1H), 7.24 (d, J=1.2 Hz, 1H), 5.35(s, 2H), 3.97 (s, 3H). [M+H]=307.12.

Example 1433-(3-Chlorophenyl)-2-methoxy-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyridine

As a mixture

¹H NMR (400 MHz, CDCl₃) δ 8.15 (d, J=2.0 Hz, 1H), 8.09 (d, J=2.3 Hz,1H), 7.99 (s, 1H), 7.82 (s, 1H), 7.56-7.49 (m, 4H), 7.42-7.32 (m, 6H),5.26 (m, 4H), 3.98 (m, 6H), 2.49 (s, 3H), 2.40 (s, 3H). [M+H]=315.22.

Example 1443-[3-(Difluoromethyl)phenyl]-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine

¹H NMR (400 MHz, DMSO-d₆) δ 8.65 (s, 1H), 8.21 (d, J=2.3 Hz, 1H), 7.95(s, 1H), 7.79 (d, J=2.3 Hz, 1H), 7.73-7.62 (m, 2H), 7.62-7.51 (m, 2H),7.23-6.90 (m, 1H), 5.42 (s, 2H), 3.86 (s, 3H). [M+H]=317.21.

Example 1453-(3-Chlorophenyl)-2-methoxy-5-(1H-pyrazol-1-ylmethyl)pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.08 (d, J=2.3 Hz, 1H), 7.76 (d, J=2.0 Hz,1H), 7.61 (d, J=2.3 Hz, 1H), 7.52 (d, J=1.2 Hz, 2H), 7.45-7.31 (m, 3H),6.33 (s, 1H), 5.35 (s, 2H), 3.94 (s, 3H). [M+H]=300.15.

Example 1463-(3-Chlorophenyl)-2-methoxy-5-{[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.72 (s, 1H), 8.24 (d, J=2.0 Hz, 1H), 7.79 (d,J=2.3 Hz, 1H), 7.56 (s, 1H), 7.49-7.31 (m, 3H), 5.50 (s, 2H), 3.96 (s,3H). [M+H]=369.17.

Example 1473-(3-Chlorophenyl)-5-[(3-Cyclopropyl-1H-1,2,4-triazol-1-yl)methyl]-2-methoxypyridine

As a mixture

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 2H), 8.18-8.12 (m, 2H), 7.81-7.32 (m,10H), 5.50 (s, 2H), 5.32 (s, 2H), 3.97-3.93 (m, 6H), 2.29-2.19 (m, 1H),2.04-1.98 (m, 1H), 1.17-0.83 (m, 8H). [M+H]=341.23.

Example 1483-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyridine

As a mixture

¹H NMR (400 MHz, CD₃OD) δ 8.58-7.32 (m, 14H), 5.43 (d, J=13.3 Hz, 4H),2.58-2.29 (m, 6H). [M+H]=351.17.

Example 1493-(3-Chlorophenyl)-2-methoxy-5-{[4-(trifluoromethyl)-1H-imidazol-1-yl]methyl}pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.48 (br s, 1H), 8.24 (br s, 1H), 8.02 (m,2H), 7.88-7.62 (m, 4H), 5.58 (m, 2H), 4.25 (s, 3H). [M+H]=368.10

Example 1503-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[1-(1H-1,2,4-triazol-1-yl)ethyl]pyridine

Step 1. 1-(5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)ethanol. Asolution of 5-(3-chlorophenyl)-6-(difluoromethoxy)nicotinaldehyde(Example 36 product from Step 2., 287 mg, 1.0 mmol) in DCM (5 mL) wascooled to 0° C. and methylmagnesium bromide (1.5 mL of a 1M solution intoluene, 1.5 mmol) was added dropwise. The mixture was warmed to roomtemperature and stirred for 30 minutes. A saturated aqueous solution ofammonium chloride was added and the mixture was extracted into DCM. Thecombined extracts were dried (Na₂SO₄), filtered and solvent removedunder reduced pressure. Purification (FCC, SiO₂, 0-60%, EtOAc/hexanes)gave 1-(5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)ethanol (231mg, 76%). [M+H]=300.1.

Step 2. A solution of1-(5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)ethanol (231 mg,0.76 mmol) and N,N-diisopropylethylamine (196 mg, 1.52 mmol) in THF (5mL) was cooled to 0° C. and methansulfonyl chloride (108 mg, 0.92 mmol)was added. The mixture was warmed to room temperature and stirred for 1hour. The LCMS confirmed the disappearance of the starting material. Allsolvents were removed in vacuo and the crude material purified (FCC,SiO₂, 0-60%, EtOAc/hexanes) to give the desired intermediate mesylate(205 mg, 70%) which was not characterized, and used directly in the nextstep.

Step 3.3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[1-(1H-1,2,4-triazol-1-yl)ethyl]pyridine.The mesylate from the previous step (90 mg, 0.23 mmol) was reacted in amanner analogous to Example 127, with the appropriated starting materialsubstitutions. Purification (FCC, SiO₂, 50-100%, EtOAc/hexanes) gave thetitle compound (56 mg, 69%).

¹H NMR (400 MHz, CD₃OD) δ 8.64 (s, 1H), 8.24 (d, J=2.3 Hz, 1H), 8.02 (s,1H), 7.91 (d, J=2.3 Hz, 1H), 7.82-7.59 (m, 1H), 7.54 (s, 1H), 7.48-7.40(m, 3H), 5.86 (d, J=7.0 Hz, 1H), 1.96 (d, J=7.0 Hz, 3H). [M+H]=351.19.

Example 1513-(3-Fluorophenyl)-2-methoxy-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyridine

As a mixture

¹H NMR (400 MHz, CD₃OD) δ 8.45 (s, 1H), 8.17 (d, J=2.3 Hz, 1H), 8.11 (d,J=2.3 Hz, 1H), 7.85 (s, 1H), 7.73 (d, J=2.3 Hz, 1H), 7.67 (d, J=2.3 Hz,1H), 7.45-7.25 (m, 6H), 7.11-7.04 (m, 2H), 5.38 (s, 2H), 5.34 (s, 2H),3.95 (m, 6H), 2.51 (s, 3H), 2.32 (s, 3H). [M+H]=299.16.

Example 1523-(3-Chlorophenyl)-2-ethoxy-5-{[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.71 (s, 1H), 8.21 (d, J=2.3 Hz, 1H), 7.79 (d,J=2.3 Hz, 1H), 7.58 (s, 1H), 7.49-7.32 (m, 3H), 5.49 (s, 2H), 4.42 (d,J=7.0 Hz, 2H), 1.34 (t, J=7.0 Hz, 3H). [M+H]=383.18.

Example 1533-(3-Chlorophenyl)-2-ethoxy-5-{[5-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.14-8.11 (m, 2H), 7.71 (d, J=2.3 Hz, 1H),7.55 (s, 1H), 7.46-7.33 (m, 3H), 5.59 (s, 2H), 4.41 (d, J=7.0 Hz, 2H),1.34 (t, J=7.2 Hz, 3H). [M+H]=383.18.

Example 1543-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(4-methyl-1H-imidazol-1-yl)methyl]pyridine

¹H NMR (400 MHz, DMSO-d₆) δ 8.25 (d, J=2.3 Hz, 1H), 7.99 (d, J=2.3 Hz,1H), 7.67-7.43 (m, 6H), 6.93 (s, 1H), 5.14 (s, 2H), 2.02 (s, 3H).[M+H]=350.18.

Example 1553-[3-(Difluoromethoxy)phenyl]-2-methoxy-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyridine

As a mixture

¹H NMR (400 MHz, CD₃OD) δ 8.44 (s, 1H), 8.19-8.09 (m, 2H), 7.74-7.65 (m,3H), 7.47-7.29 (m, 6H), 7.17-7.10 (m, 2H), 7.04-6.64 (m, 2H), 5.40-5.37(m, 2H), 5.34 (s, 2H), 3.94 (m, 6H), 2.51 (s, 3H), 2.32 (s, 3H).[M+H]=347.23.

Example 1561-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-1,2,4-triazole-3-carbonitrile

¹H NMR (400 MHz, CD₃OD) δ 8.76 (s, 1H), 8.29 (d, J=2.3 Hz, 1H), 7.97 (d,J=2.3 Hz, 1H), 7.82-7.40 (m, 5H), 5.58 (s, 2H). [M+H]=362.01.

Example 1573-(3-Chlorophenyl)-2-(difluoromethoxy)-5-{[3-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.58 (s, 1H), 8.25 (d, J=2.3 Hz, 1H), 7.91 (d,J=2.3 Hz, 1H), 7.80-7.40 (m, 5H), 5.48 (s, 2H), 4.46 (s, 2H), 3.36 (s,3H). [M+H]=381.17.

Example 1583-(3-Chlorophenyl)-2-(difluoromethoxy)-5-{[5-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.23 (d, J=2.3 Hz, 1H), 7.94 (s, 1H), 7.90 (d,J=2.3 Hz, 1H), 7.80-7.40 (m, 5H), 5.51 (s, 2H), 4.71 (s, 2H), 3.37 (s,3H). [M+H]=381.17.

Example 1593-[3-(Difluoromethoxy)phenyl]-2-methoxy-5-{[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.71 (s, 1H), 8.24 (d, J=2.3 Hz, 1H), 7.79 (d,J=2.3 Hz, 1H), 7.47-7.36 (m, 2H), 7.33 (d, J=2.0 Hz, 1H), 7.17-7.11 (m,1H), 7.03-6.64 (m, 1H), 5.50 (s, 2H), 3.96 (s, 3H). [M+H]=401.19.

Example 1603-[3-(Difluoromethoxy)phenyl]-2-methoxy-5-{[5-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.15 (d, J=2.3 Hz, 1H), 8.12 (s, 1H), 7.72 (d,J=2.3 Hz, 1H), 7.43 (d, J=8.2 Hz, 1H), 7.37 (s, 1H), 7.30 (s, 1H),7.16-7.11 (m, 1H), 7.03-6.65 (m, 1H), 5.60 (s, 2H), 3.95 (s, 3H).[M+H]=401.19.

Example 1613-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1H-1,2,3,4-tetrazol-1-ylmethyl)pyridine

¹H NMR (400 MHz, CDCl₃) δ 8.65 (s, 1H), 8.23 (d, J=2.3 Hz, 1H), 7.73 (d,J=2.3 Hz, 1H), 7.39 (s, 5H), 5.64 (s, 2H). [M+H]=338.15.

Example 1623-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(2H-1,2,3,4-tetrazol-2-ylmethyl)pyridine

¹H NMR (400 MHz, CDCl₃) δ 8.55 (s, 1H), 8.30 (d, J=2.3 Hz, 1H), 7.82 (d,J=2.7 Hz, 1H), 7.73-7.34 (m, 5H), 5.85 (s, 2H). [M+H]=338.15.

Example 1633-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.72 (s, 1H), 8.21 (d, J=2.38 Hz, 1H), 7.81(d, J=2.38 Hz, 1H), 7.48-7.35 (m, 3H), 7.18-7.06 (m, 1H), 7.06-6.60 (m,1H), 5.50 (s, 2H), 4.42 (q, J=7.07 Hz, 2H), 1.35 (t, J=7.09 Hz, 3H).[M+H]=415.21.

Example 1643-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[5-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.13 (s, 2H), 7.74 (d, J=2.51 Hz, 1H),7.49-7.42 (m, 1H), 7.40-7.34 (m, 2H), 7.14 (dd, J=7.40, 1.76 Hz, 1H),7.05-6.63 (m, 1H) 5.60 (s, 2H), 4.41 (q, J=7.03 Hz, 2H), 1.35 (t, J=7.09Hz, 3H). [M+H]=415.21.

Example 1653-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[3-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.56 (s, 1H), 8.17 (d, J=2.3 Hz, 1H), 7.76 (d,J=2.3 Hz, 1H), 7.49-7.35 (m, 3H), 7.13 (td, J=2.0, 7.8 Hz, 1H),7.04-6.63 (m, 1H), 5.41 (s, 2H), 4.47 (s, 2H), 4.41 (q, J=7.0 Hz, 2H),3.37 (s, 3H), 1.35 (t, J=7.2 Hz, 3H). [M+H]=391.28.

Example 1663-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[5-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.15 (d, J=2.3 Hz, 1H), 7.93 (s, 1H), 7.75 (d,J=2.3 Hz, 1H), 7.49-7.33 (m, 3H), 7.12 (tdd, J=1.0, 2.1, 7.7 Hz, 1H),7.04-6.60 (m, 1H), 5.44 (s, 2H), 4.70 (s, 2H), 4.40 (q, J=7.0 Hz, 2H),3.38 (s, 3H), 1.34 (t, J=7.0 Hz, 3H). [M+H]=391.25.

Example 1675-[(4-Chloro-1H-pyrazol-1-yl)methyl]-3-[3-(difluoromethoxy)phenyl]-2-methoxypyridine

¹H NMR (400 MHz, CD₃OD) δ 8.11 (d, J=2.7 Hz, 1H), 7.84 (s, 1H), 7.67 (d,J=2.3 Hz, 1H), 7.49-7.30 (m, 4H), 7.15-7.10 (m, 1H), 7.03-6.64 (m, 1H),5.30 (s, 2H), 3.94 (s, 3H). [M+H]=366.16.

Example 1681-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazole-3-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.14 (d, J=2.3 Hz, 1H), 7.78 (d, J=2.3 Hz,1H), 7.70 (d, J=2.3 Hz, 1H), 7.57 (s, 1H), 7.48-7.43 (m, 1H), 7.41-7.32(m, 2H), 6.76 (d, J=2.3 Hz, 1H), 5.39 (s, 2H), 4.41 (q, J=7.0 Hz, 2H),1.34 (t, J=7.0 Hz, 3H). [M+H]=357.29.

Example 169 Ethyl1-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-4-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ 8.48 (s, 1H), 8.20 (d, J=2.35 Hz, 1H),7.87-7.76 (m, 2H), 7.57 (s, 1H), 7.56-7.32 (m, 3H), 5.35 (s, 2H), 4.18(q, J=7.04 Hz, 2H), 3.87 (s, 3H), 1.23 (t, J=7.04 Hz, 3H). [M+H]=372.13.

Example 1701-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-4-carbonitrile

¹H NMR (400 MHz, DMSO-d₆) δ 8.67 (s, 1H), 8.20 (d, J=1.96 Hz, 1H), 8.05(s, 1H), 7.81 (d, J=1.96 Hz, 1H), 7.61-7.31 (m, 4H), 5.39 (s, 2H), 3.87(s, 3H). [M+H]=328.08.

Example 1712-Methoxy-3-(pyridin-4-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine

¹H NMR (400 MHz, DMSO-d₆) δ 8.83 (d, J=3.91 Hz, 2H), 8.67 (s, 1H), 8.35(s, 1H), 8.00 (dd, J=13.30, 7.83 Hz, 4H), 5.45 (s, 2H), 3.93 (s, 3H).[M+H]=298.15.

Example 172N-(1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazol-4-yl)acetamide

The title compound was isolated as a bi-product from Example 236. ¹H NMR(400 MHz, CD₃OD) δ 8.04 (d, J=1.57 Hz, 1H), 7.95 (s, 1H), 7.57 (d,J=1.57 Hz, 1H), 7.47 (s, 1H), 7.44 (s, 1H), 7.34-7.29 (m, 3H), 5.22 (s,2H), 3.88 (s, 3H), 2.01 (s, 3H). [M+H]=357.32.

Example 1733-(3-Chlorophenyl)-5-(1H-imidazol-1-ylmethyl)-2-methoxypyridine

¹H NMR (400 MHz, DMSO-d₆) δ 8.21 (d, J=2.3 Hz, 1H), 7.84-7.77 (m, 2H),7.58 (d, J=0.8 Hz, 1H), 7.53-7.39 (m, 3H), 7.26 (s, 1H), 6.87 (s, 1H),5.17 (s, 2H), 3.93-3.78 (m, 3H). [M+H]=301.12.

Example 1742-(Difluoromethoxy)-3-(3-fluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine

¹H NMR (400 MHz, DMSO-d₆) δ 8.73-8.62 (m, 1H), 8.32-8.20 (m, 1H),8.06-7.96 (m, 1H), 7.93-7.85 (m, 1H), 7.75-7.66 (m, 1H), 7.60-7.49 (m,1H), 7.44-7.33 (m, 1H), 7.28 (dt, J=2.3, 8.6 Hz, 1H), 5.49 (s, 1H), 5.44(s, 2H). [M+H]=321.14.

Example 1752-(Difluoromethoxy)-3-(3-methoxyphenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine

¹H NMR (400 MHz, DMSO-d₆) δ 8.71-8.62 (m, 1H), 8.03-7.92 (m, 1H),7.91-7.87 (m, 1H), 7.73-7.68 (m, 1H), 7.55-7.51 (m, 1H), 7.43-7.37 (m,1H), 7.10-7.05 (m, 1H), 7.03-6.96 (m, 1H), 5.75 (s, 1H), 5.49 (s, 1H),5.44 (s, 1H), 3.78 (s, 3H). [M+H]=333.24.

Example 1762-(Difluoromethoxy)-5-(1H-1,2,4-triazol-1-ylmethyl)-3-[3-(trifluoromethoxy)phenyl]pyridine

¹H NMR (400 MHz, DMSO-d₆) δ 8.67 (d, J=9.8 Hz, 1H), 8.33-8.19 (m, 2H),8.04 (d, J=2.3 Hz, 1H), 7.98 (d, J=3.1 Hz, 1H), 7.88 (d, J=0.8 Hz, 1H),7.70 (s, 1H), 7.67-7.39 (m, 2H), 5.50 (s, 1H), 5.44 (s, 1H).[M+H]=386.14.

Example 1771-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1,2-dihydropyridin-2-one

¹H NMR (400 MHz, CDCl₃) δ 8.16 (d, J=1.96 Hz, 1H), 7.65 (d, J=1.96 Hz,1H), 7.52 (s, 1H), 7.42-7.32 (m, 1H), 7.36-7.29 (m, 4H), 6.61 (d, J=9.00Hz, 1H), 6.18 (t, J=6.46 Hz, 1H), 5.12 (s, 2H), 3.96 (s, 3H).[M+H]=327.17.

Example 1785-[(4-Chloro-1H-pyrazol-1-yl)methyl]-3-(3-chlorophenyl)-2-methoxypyridine

¹H NMR (400 MHz, DMSO-d₆) δ 8.20 (s, 1H), 8.10 (s, 1H), 7.80 (s, 1H),7.60 (s, 1H), 7.55 (s, 1H), 7.50-7.40 (m, 3H), 5.24 (s, 2H), 3.86 (s,3H). [M+H]=334.07.

Example 1793-(3-Chlorophenyl)-2-methoxy-5-[(4-methyl-1H-pyrazol-1-yl)methyl]pyridine

¹H NMR (400 MHz, DMSO-d₆) δ 8.15 (s, 1H), 7.67 (s, 1H), 7.61-7.58 (m,1H), 7.54-7.36 (m, 4H), 7.10 (s, 1H), 5.14 (s, 2H), 3.85 (s, 3H), 3.60(s, 3H). [M+H]=314.10.

Example 1803-(3-Chlorophenyl)-2-methoxy-5-[(4-nitro-1H-pyrazol-1-yl)methyl]pyridine

¹H NMR (400 MHz, DMSO-d₆) δ 9.05 (s, 1H), 8.06 (s, 1H), 7.61 (s, 1H),7.57 (s, 1H), 7.52-7.38 (m, 4H), 5.54 (s, 2H), 3.85 (s, 3H).[M+H]=345.09.

Example 1813-(3-Chlorophenyl)-2-methoxy-5-[(4-nitro-1H-pyrazol-1-yl)methyl]pyrazine

¹H NMR (400 MHz, CD₃OD) δ 8.76 (s, 1H), 8.19 (s, 1H), 8.13 (s, 1H), 8.02(s, 1H), 8.01-7.91 (m, 1H), 7.45-7.35 (m, 2H), 5.52 (s, 2H), 4.06 (s,3H). [M+H]=346.70.

Example 1823-(3-Chlorophenyl)-2-methoxy-5-(1H-pyrazol-1-ylmethyl)pyrazine

¹H NMR (400 MHz, CD₃OD) δ 8.76 (s, 1H), 8.19 (s, 1H), 8.13 (s, 1H), 8.02(s, 1H), 8.01-7.91 (m, 2H), 7.45-7.35 (m, 2H), 5.52 (s, 2H), 4.06 (s,3H). [M+H]=301.11.

Example 1833-(3-Chlorophenyl)-5-(1H-imidazol-1-ylmethyl)-2-methoxypyrazine

¹H NMR (400 MHz, CD₃OD) δ 9.13 (br s, 1H), 8.33 (s, 1H), 8.05-7.89 (m,2H), 7.73 (br s, 1H), 7.57 (br s, 1H), 7.48-7.35 (m, 2H), 5.60 (s, 2H),4.09 (s, 3H). [M+H]=303.11.

Example 1843-(3-Chlorophenyl)-2-methoxy-5-[(4-methyl-1H-pyrazol-1-yl)methyl]pyrazine

¹H NMR (400 MHz, CD₃OD) δ 8.07-7.96 (m, 2H), 7.94 (s, 1H), 7.58 (br s,1H), 7.42 (d, J=3.91 Hz, 2H), 7.34 (s, 1H), 5.39 (s, 2H), 4.04 (s, 3H),2.09 (s, 3H). [M+H]=315.10.

Example 1853-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyrazine

as a mixture

¹H NMR (400 MHz, CD₃OD) δ 8.53 (s, 1H), 8.15 (s, 1H), 8.14 (s, 1H),7.96-7.90 (m, 2H), 7.86 (t, J=2.0 Hz, 1H), 7.85-7.82 (m, 2H), 7.46 (dt,J=1.6, 8.0 Hz, 2H), 7.21 (s, 1H), 7.19 (s, 1H), 7.04-6.64 (m, 2H), 5.50(s, 2H), 5.47 (s, 2H), 4.57-4.45 (m, 4H), 2.63 (s, 3H), 2.32 (s, 3H),1.44 (t, J=7.0 Hz, 6H). [M+H]=362.15.

Example 1865-[(3-Cyclopropyl-1H-1,2,4-triazol-1-yl)methyl]-3-[3-(difluoromethoxy)phenyl]-2-ethoxypyrazine

as a mixture

¹H NMR (400 MHz, CD₃OD) δ 8.46 (s, 1H), 8.14 (s, 2H), 7.99-7.92 (m, 2H),7.89-7.85 (m, 2H), 7.78 (s, 2H), 7.48-7.44 (m, 2H), 7.21-7.18 (m, 1H),7.04-6.62 (m, 2H), 5.61 (s, 2H), 5.45 (s, 2H), 4.58-4.46 (m, 4H),2.41-2.30 (m, 1H), 1.99 (tt, J=5.2, 8.3 Hz, 1H), 1.45 (dt, J=1.6, 7.0Hz, 6H), 1.17-1.09 (m, 2H), 1.07-1.01 (m, 2H), 0.98-0.90 (m, 2H),0.90-0.85 (m, 2H). [M+H]=388.15.

Example 1873-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyrazine

¹H NMR (400 MHz, CD₃OD) δ 8.80 (s, 1H), 8.23 (s, 1H), 7.93-7.90 (m, 1H),7.86 (t, J=2.0 Hz, 1H), 7.46 (t, J=8.0 Hz, 1H), 7.20 (dd, J=2.0, 8.2 Hz,1H), 7.03-6.62 (m, 1H), 5.64 (s, 2H), 4.52 (q, J=7.0 Hz, 2H), 1.45 (t,J=7.0 Hz, 3H). [M+H]=416.12.

Example 1883-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[5-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyrazine

¹H NMR (400 MHz, CD₃OD) δ 8.19 (s, 1H), 8.12 (s, 1H), 7.95-7.87 (m, 1H),7.83 (t, J=2.0 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.19 (dd, J=2.2, 8.0 Hz,1H), 7.02-6.59 (m, 1H), 5.74 (s, 2H), 4.52 (q, J=7.3 Hz, 2H), 1.45 (t,J=7.0 Hz, 3H). [M+H]=416.12.

Example 1893-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[3-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyrazine

¹H NMR (400 MHz, CD₃OD) δ 8.63 (s, 1H), 8.18 (s, 1H), 7.96-7.91 (m, 1H),7.85 (t, J=2.2 Hz, 1H), 7.45 (t, J=8.2 Hz, 1H), 7.20 (dd, J=2.0, 8.2 Hz,1H), 7.05-6.62 (m, 1H), 5.54 (s, 2H), 4.51 (q, J=7.0 Hz, 2H), 4.46 (s,3H), 4.30 (s, 2H), 1.44 (t, J=7.0 Hz, 3H). [M+H]=392.26.

Example 1903-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[5-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyrazine

¹H NMR (400 MHz, CD₃OD) δ 8.14 (s, 1H), 7.95-7.91 (m, 2H), 7.84 (d,J=2.0 Hz, 1H), 7.46 (t, J=8.0 Hz, 1H), 7.20 (dd, J=2.2, 8.0 Hz, 1H),7.03-6.63 (m, 1H), 5.60 (s, 2H), 4.79 (s, 2H), 4.51 (q, J=7.0 Hz, 2H),3.38 (s, 3H), 1.44 (t, J=7.0 Hz, 3H). [M+H]=392.15.

Example 191 Methyl1-((6-(3-(difluoromethoxy)phenyl)-5-ethoxypyrazin-2-yl)methyl)-1H-1,2,4-triazole-3-carboxylate

¹H NMR (400 MHz, CD₃OD) δ 8.78 (s, 1H), 8.23 (s, 1H), 7.92 (td, J=1.4,7.8 Hz, 1H), 7.84 (t, J=2.0 Hz, 1H), 7.45 (t, J=8.0 Hz, 1H), 7.19 (dd,J=2.3, 8.2 Hz, 1H), 7.03-6.63 (m, 1H), 5.63 (s, 2H), 4.51 (q, J=7.0 Hz,2H), 3.91 (s, 3H), 1.44 (t, J=7.2 Hz, 3H). [M+H]=406.15.

Example 192 Methyl1-((6-(3-(difluoromethoxy)phenyl)-5-ethoxypyrazin-2-yl)methyl)-1H-1,2,4-triazole-5-carboxylate

¹H NMR (400 MHz, CD₃OD) δ 8.63 (s, 1H), 8.18 (s, 1H), 7.95-7.92 (m, 1H),7.87-7.85 (m, 1H), 7.45 (t, J=8.2 Hz, 1H), 7.20 (dd, J=2.0, 8.2 Hz, 1H),7.03-6.64 (m, 1H), 5.54 (s, 2H), 4.51 (q, J=7.0 Hz, 2H), 3.35 (s, 3H),1.44 (t, J=7.0 Hz, 3H). [M+H]=406.26.

Example 1933-(3-(Difluoromethoxy)phenyl)-2-ethoxy-5-((3-nitro-1H-1,2,4-triazol-1-yl)methyl)pyrazine

¹H NMR (400 MHz, CD₃OD) δ 8.82 (s, 1H), 8.28 (s, 1H), 7.92 (td, J=1.4,7.8 Hz, 1H), 7.86 (t, J=2.0 Hz, 1H), 7.46 (t, J=8.0 Hz, 1H), 7.20 (dd,J=2.7, 8.2 Hz, 1H), 7.03-6.62 (m, 1H), 5.67 (s, 2H), 4.53 (q, J=7.0 Hz,2H), 1.45 (t, J=7.0 Hz, 3H). [M+H]=393.15.

Example 1943-(3-(Difluoromethoxy)phenyl)-2-ethoxy-5-((5-nitro-1H-1,2,4-triazol-1-yl)methyl)pyrazine

¹H NMR (400 MHz, CD₃OD) δ 8.23 (s, 1H), 8.10 (s, 1H), 7.80 (td, J=1.4,7.8 Hz, 1H), 7.73 (t, J=2.3 Hz, 1H), 7.43 (t, J=8.0 Hz, 1H), 7.18 (dd,J=2.0, 8.2 Hz, 1H), 7.02-6.61 (m, 1H), 6.01 (s, 2H), 4.51 (q, J=7.0 Hz,2H), 1.44 (t, J=7.0 Hz, 3H). [M+H]=393.21.

Example 195 Methyl1-{[6-(3-chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-1,2,4-triazole-5-carboxylate

¹H NMR (400 MHz, CD₃OD) δ 8.19 (s, 1H), 8.09 (s, 1H), 7.94 (td, J=1.1,2.1 Hz, 1H), 7.93-7.86 (m, 1H), 7.43-7.34 (m, 2H), 5.99 (s, 2H),4.08-4.04 (m, 3H), 3.99-3.95 (m, 3H). [M+H]=360.18.

Example 196 Methyl1-({6-[3-(difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)-1H-1,2,4-triazole-3-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ 8.88 (s, 1H), 8.35 (s, 1H), 7.83 (td, J=1.4,7.8 Hz, 1H), 7.72-7.68 (m, 1H), 7.52 (t, J=8.0 Hz, 1H), 7.43-7.04 (m,2H), 5.66 (s, 2H), 3.99 (s, 3H), 3.29 (s, 3H). [M+H]=392.16.

Example 197 Methyl1-{[6-(3-chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-1H-1,2,4-triazole-3-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ 8.89 (s, 1H), 8.32 (s, 1H), 7.99-7.96 (m,1H), 7.96-7.90 (m, 1H), 7.52-7.46 (m, 2H), 5.64 (s, 2H), 4.45 (q, J=7.0Hz, 2H), 3.83-3.77 (m, 3H), 1.39-1.34 (m, 3H). [M+H]=374.18.

Example 1981-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-imidazole-4-carboxamide

Step 1. Methyl1-((5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)methyl)-1H-imidazole-4-carboxylatewas prepared in a manner analogous to Example 127.

Step 2.1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-imidazole-4-carboxamide.To a solution of methyl1-((5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)methyl)-1H-imidazole-4-carboxylatein 7 N ammonia in MeOH (4 mL) was added NaCN (5 mg). Reaction mixturewas heated 24 h at 130° C. LC-MS confirms the disappearance of startingmaterial. The reaction mixture was concentrated under reduced pressure.Purification (FCC, SiO₂, 0-1%, EtOAc/MeOH) gave the title compound. ¹HNMR (400 MHz, DMSO-d₆) δ 8.18 (d, J=2.3 Hz, 1H), 8.04 (s, 1H), 7.92 (d,J=2.3 Hz, 1H), 7.68 (s, 1H), 7.61 (s, 1H), 7.57-7.55 (m, 1H), 7.53-7.43(m, 3H), 5.58 (s, 2H), 3.55 (s, 1H), 3.15 (d, J=5.1 Hz, 1H).[M+H]=379.15.

Example 199(1-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol

To a solution of methyl1-((6-(3-chlorophenyl)-5-methoxypyrazin-2-yl)methyl)-1H-1,2,4-triazole-3-carboxylate(Example 127, 77.00 mg, 0.21 mmol), in THF (1 mL) was added lithiumborohydride (4.66 mg, 0.21 mmol). The mixture was stirred at roomtemperature for 3 hr. The mixture was diluted with water and extractedinto DCM. The combined extracts were dried (Na₂SO₄) and concentratedunder reduced pressure. Purification (FCC, SiO₂, 0-5% DCM/MeOH) affordedthe title compound (50 mg; 70%). ¹H NMR (400 MHz, CD₃OD) δ 8.61 (s, 1H),8.21 (s, 1H), 8.02 (td, J=1.1, 2.1 Hz, 1H), 8.00-7.92 (m, 1H), 7.45-7.38(m, 2H), 5.53 (s, 2H), 4.59 (s, 2H), 4.06 (s, 3H). [M+H]=332.15.

Examples 200-212 were prepared in a manner analogous to Example 199,with the appropriate starting materials and reagent substitutions.

Example 200(1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol

¹H NMR (400 MHz, CD₃OD) δ 8.55 (s, 1H), 8.26 (d, J=2.3 Hz, 1H), 7.93 (d,J=2.7 Hz, 1H), 7.82-7.38 (m, 5H), 5.46 (s, 2H), 4.59 (s, 2H).[M+H]=367.18.

Example 201[1-({5-[3-(Difluoromethoxy)phenyl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol

¹H NMR (400 MHz, CD₃OD) δ 8.52 (s, 1H), 8.17 (d, J=2.3 Hz, 1H), 7.76 (d,J=2.3 Hz, 1H), 7.49-7.34 (m, 3H), 7.13 (td, J=2.0, 7.8 Hz, 1H),7.02-6.65 (m, 1H), 5.39 (s, 2H), 4.59 (s, 2H), 4.40 (q, J=7.2 Hz, 2H),1.34 (t, J=7.0 Hz, 3H). [M+H]=377.25.

Example 202[1-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol

¹H NMR (400 MHz, CD₃OD) δ 8.53 (s, 1H), 8.20 (d, J=2.7 Hz, 1H), 7.76 (d,J=2.3 Hz, 1H), 7.48-7.35 (m, 2H), 7.32 (t, J=1.8 Hz, 1H), 7.16-7.11 (m,1H), 7.03-6.65 (m, 1H), 5.49 (s, 1H), 4.59 (s, 2H), 3.95 (s, 3H).[M+H]=363.23.

Example 203(1-((5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl)methyl)-1H-1,2,4-triazol-3-yl)methanol

¹H NMR (400 MHz, CD₃OD) δ 8.53 (s, 1H), 8.18 (d, J=2.7 Hz, 1H), 7.75 (d,J=2.7 Hz, 1H), 7.60-7.56 (m, 1H), 7.49-7.45 (m, 1H), 7.42-7.33 (m, 2H),5.39 (s, 2H), 4.59 (s, 2H), 4.42 (q, J=7.0 Hz, 2H), 1.34 (t, J=7.0 Hz,3H). [M+H]=345.22.

Example 204(1-{[6-(Difluoromethoxy)-5-(3-ethoxyphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol

¹H NMR (400 MHz, CD₃OD) δ 8.56 (s, 1H), 8.22 (d, J=2.3 Hz, 1H), 7.89 (d,J=2.3 Hz, 1H), 7.61 (t, J=1.0 Hz, 1H), 7.38-7.31 (m, 1H), 7.10-7.03 (m,2H), 6.95 (ddd, J=1.0, 2.4, 8.3 Hz, 1H), 5.46 (s, 2H), 4.59 (s, 2H),4.07 (q, J=7.0 Hz, 2H), 1.40 (t, J=7.0 Hz, 3H). [M+H]=377.25.

Example 205[1-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol

¹H NMR (400 MHz, CD₃OD) δ 8.53 (s, 1H), 8.28 (d, J=2.3 Hz, 1H),8.24-8.21 (m, 1H), 7.89 (d, J=2.3 Hz, 1H), 7.76-7.37 (m, 2H), 7.20-7.17(m, 1H), 5.41 (s, 2H), 4.59 (s, 2H), 3.98 (s, 3H). [M+H]=364.22.

Example 206[1-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol

¹H NMR (400 MHz, CD₃OD) δ 8.54 (s, 1H), 8.26 (d, J=2.3 Hz, 1H), 8.24(dd, J=0.8, 5.5 Hz, 1H), 7.89 (d, J=2.3 Hz, 1H), 7.77-7.56 (m, 1H),7.44-7.41 (m, 1H), 7.23-7.20 (m, 1H), 5.41 (s, 2H), 4.59 (s, 2H), 4.45(q, J=7.0 Hz, 2H), 1.37 (t, J=7.0 Hz, 3H). [M+H]=378.20.

Example 207(1-{[6-(Difluoromethoxy)-5-[2-(difluoromethoxy)pyridin-4-yl]pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol

¹H NMR (400 MHz, CD₃OD) δ 8.56 (s, 1H), 8.35-8.28 (m, 2H), 8.05 (d,J=2.3 Hz, 1H), 7.83-7.41 (m, 2H), 7.41-7.39 (m, 1H), 7.19-7.17 (m, 1H),5.49 (s, 2H), 4.59 (s, 2H). [M+H]=400.21.

Example 208[1-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol

¹H NMR (400 MHz, CD₃OD) δ 8.60 (s, 1H), 8.18 (s, 1H), 7.93 (td, J=1.4,7.8 Hz, 1H), 7.86 (t, J=2.0 Hz, 1H), 7.46 (t, J=8.0 Hz, 1H), 7.20 (dd,J=2.0, 8.2 Hz, 1H), 7.04-6.64 (m, 1H), 5.52 (s, 2H), 4.59 (s, 2H), 4.51(q, J=7.3 Hz, 2H), 1.44 (t, J=7.0 Hz, 3H). [M+H]=378.25.

Example 209[1-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)-1H-1,2,4-triazol-5-yl]methanol

¹H NMR (400 MHz, CD₃OD) δ 8.14 (s, 1H), 7.90 (s, 1H), 7.93-7.89 (m, 1H),7.83 (t, J=2.0 Hz, 1H), 7.46 (t, J=8.0 Hz, 1H), 7.19 (dd, J=2.7, 7.8 Hz,1H), 7.05-6.62 (m, 1H), 5.65 (s, 2H), 4.91 (s, 2H), 4.50 (q, J=7.0 Hz,2H), 1.44 (t, J=7.0 Hz, 3H). [M+H]=378.15.

Example 210(1-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-1,2,4-triazol-5-yl)methanol

¹H NMR (400 MHz, CD₃OD) δ 8.16 (s, 1H), 8.02-7.99 (m, 1H), 7.94 (ddd,J=1.8, 3.5, 5.3 Hz, 1H), 7.92-7.89 (m, 1H), 7.44-7.39 (m, 2H), 5.66 (s,2H), 4.90 (s, 2H), 4.06 (s, 3H). [M+H]=332.18.

Example 211[1-({6-[3-(Difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}-methyl)-1H-1,2,4-triazol-3-yl]methanol

¹H NMR (400 MHz, DMSO-d₆) δ 8.59 (s, 1H), 8.27 (s, 1H), 7.88-7.83 (m,1H), 7.76-7.71 (m, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.45-7.06 (m, 2H), 5.50(s, 2H), 5.16 (t, J=6.1 Hz, 1H), 4.36 (d, J=6.3 Hz, 2H), 3.98 (s, 3H).[M+H]=364.14.

Example 212(1-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol

¹H NMR (400 MHz, DMSO-d₆) δ 8.60 (s, 1H), 8.24 (s, 1H), 8.02-7.99 (m,1H), 7.99-7.93 (m, 1H), 7.54-7.48 (m, 2H), 5.49 (s, 2H), 5.16 (t, J=6.1Hz, 1H), 4.45 (q, J=7.0 Hz, 2H), 4.36 (d, J=5.9 Hz, 2H), 1.36 (t, J=7.0Hz, 3H). [M+H]=346.25.

Example 2133-(3-Chlorophenyl)-2-methoxy-5-[(3-methoxy-1H-1,2,4-triazol-1-yl)methyl]pyridine

Step 1.3-(3-Chlorophenyl)-2-methoxy-5-((3-nitro-1H-1,2,4-triazol-1-yl)methyl)pyridine.The title compound was prepared in a manner analogous to Example 127with the appropriate starting material substitutions.

Step 2.3-(3-Chlorophenyl)-2-methoxy-5-[(3-methoxy-1H-1,2,4-triazol-1-yl)methyl]pyridine.To a solution of3-(3-chlorophenyl)-2-methoxy-5-((3-nitro-1H-1,2,4-triazol-1-yl)methyl)pyridine(135 mg, 0.39 mmol), in methanol (3 mL) was added sodium methoxide (63mg, 1.17 mmol). The mixture was stirred at 60° C. for 16 h. The LCMSshowed approximately 70% conversion. All solvents removed under reducedpressure, the residue dissolved in DCM (50 mL) and water (50 mL), thelayers shaken and separated and the aqueous layer extracted into DCM(3×50 mL). The combined extracts were dried (MgSO₄), filtered andsolvent removed under reduced pressure. Purification (FCC, SiO₂, 0-100%EtOAc/DCM) afforded the title compound (72 mg, 56%). ¹H NMR (400 MHz,DMSO-d₆) δ 8.33 (s, 1H), 8.19 (d, J=2.0 Hz, 1H), 7.79 (d, J=2.3 Hz, 1H),7.58 (s, 1H), 7.52-7.38 (m, 3H), 5.23 (s, 2H), 3.87 (s, 3H), 3.79 (s,3H). [M+H]=331.21.

Examples 214-216 were prepared in a manner analogous to Example 213,with the appropriate starting materials and reagent substitutions.

Example 2143-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(3-methoxy-1H-1,2,4-triazol-1-yl)methyl]pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.27 (s, 1H), 8.24 (d, J=2.3 Hz, 1H), 7.91 (d,J=2.3 Hz, 1H), 7.82-7.61 (m, 1H), 7.57 (s, 1H), 7.49-7.40 (m, 3H), 5.32(s, 2H), 3.92 (s, 3H). [M+H]=367.16.

Example 2153-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(5-methoxy-1H-1,2,4-triazol-1-yl)methyl]pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.17 (d, J=2.0 Hz, 1H), 7.84 (d, J=2.3 Hz,1H), 7.61-7.39 (m, 6H), 5.21 (s, 2H), 4.12 (s, 3H). [M+H]=367.16.

Example 2163-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(3-ethoxy-1H-1,2,4-triazol-1-yl)methyl]pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.28-8.21 (m, 2H), 7.91 (d, J=2.3 Hz, 1H),7.84-7.60 (m, 1H), 7.56 (s, 1H), 7.49-7.40 (m, 3H), 5.31 (s, 2H), 4.26(q, J=7.0 Hz, 2H), 1.35 (t, J=7.0 Hz, 3H). [M+H]=380.18.

Example 2171-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-amine

Step 1.3-(3-(Difluoromethoxy)phenyl)-2-methoxy-5-((3-nitro-1H-1,2,4-triazol-1-yl)methyl)pyridine.The title compound was prepared in a manner analogous to Example 127with the appropriate starting material substitutions.

Step 2.1-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-amine.To a solution of3-(3-(difluoromethoxy)phenyl)-2-methoxy-5-((3-nitro-1H-1,2,4-triazol-1-yl)methyl)pyridine(331.00 mg, 0.88 mmol) in AcOH (6 mL), and water (2 mL) was added zinc(573.57 mg, 8.77 mmol). The mixture was stirred at 50° C. for 1 hr. Thesolvent was removed under reduced pressure to afford a white solid. Thecrude solid was dissolved in DCM (50 mL), sonicated and filtered(repeated twice). The combined DCM extracts were washed with a saturatedaqueous solution of sodium bicarbonate and the layers separated. Theorganic layers were combined, dried (Na₂SO₄) and concentrated underreduced pressure. The resulting solid was triturated with hexanes togive the title compound (287 mg, 94%). ¹H NMR (400 MHz, CD₃OD) δ 8.15(d, J=2.7 Hz, 1H), 8.13 (s, 1H), 7.71 (d, J=2.3 Hz, 1H), 7.47-7.36 (m,2H), 7.33 (t, J=1.8 Hz, 1H), 7.16-7.11 (m, 1H), 7.04-6.65 (m, 1H), 5.19(s, 2H), 3.95 (s, 3H). [M+H]=348.22.

Examples 218-237 were prepared in a manner analogous to Example 217,with the appropriate starting materials and reagent substitutions.

Example 2181-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine

¹H NMR (400 MHz, DMSO-d₆) δ 8.17 (d, J=2.3 Hz, 1H), 8.09 (s, 1H), 7.76(d, J=2.3 Hz, 1H), 7.58 (d, J=1.6 Hz, 1H), 7.51-7.42 (m, 3H), 5.26 (s,2H), 5.11 (s, 2H), 3.88 (s, 3H). [M+H]=316.21.

Example 2191-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine

¹H NMR (400 MHz, CD₃OD) δ 8.11 (d, J=2.3 Hz, 1H), 8.06 (s, 1H), 7.78 (d,J=2.3 Hz, 1H), 7.73-7.50 (m, 1H), 7.47 (s, 1H), 7.41-7.30 (m, 3H), 5.15(s, 2H). [M+H]=352.17.

Example 2201-{[5-(3-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine

Step 1.3-Bromo-2-methoxy-5-((3-nitro-1H-1,2,4-triazol-1-yl)methyl)pyridine.Title compound was prepared in a manner analogous to Intermediate 5 withthe appropriate starting materials and reagent substitutions.[M+H]=314.24316.25.

Step 2.1-((5-(3-Fluorophenyl)-6-methoxypyridin-3-yl)methyl)-1H-1,2,4-triazol-3-amine.To a solution of3-bromo-2-methoxy-5-((3-nitro-1H-1,2,4-triazol-1-yl)methyl)pyridine (60mg, 0.191 mmol) in AcOH (3 mL), and water (1 mL) was added zinc (124 mg,1.91 mmol). The mixture was stirred at 50° C. for 1 hr. The solvent wasremoved under reduced pressure to afford a white solid. The crude solidwas dissolved in DCM (50 mL), sonicated and filtered (repeated twice).The combined DCM extracts were washed with a saturated aqueous solutionof sodium bicarbonate and the layers separated. The organic layers werecombined, dried (Na₂SO₄) and concentrated under reduced pressure. Thecrude intermediate and (3-fluorophenyl) boronic (42 mg, 0.3 mmol)dissolved in mixture of water (2 mL), and ACN (4 mL) were added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (8 mg, 0.01mmol) followed by sodium carbonate (53 mg, 0.5 mmol). The mixture wasirradiated under microwaves for 15 minutes at 100° C. The reactionmixture was diluted with water and extracted with DCM (3×5 mL). Thecombined organic phase was dried (Na₂SO₄), filtered, and concentratedunder reduced pressure. Purification (FCC, SiO₂, 0-10% DCM/MeOH)afforded the title compound (49.7 mg, 89%). ¹H NMR (400 MHz, CD₃OD) δ8.13 (br s, 1H), 7.71 (br s, 1H), 7.63-7.23 (m, 4H), 7.08 (br s, 1H),5.19 (m, 2H), 3.95 (s, 3H). [M+H]=300.27.

Examples 221-223 were prepared in a manner analogous to Example 220,with the appropriate starting material and reagent substitutions.

Example 2211-{[6-Methoxy-5-(3-methoxyphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine

¹H NMR (400 MHz, CD₃OD) δ 8.12 (s, 2H), 7.67 (d, J=2.3 Hz, 1H), 7.31(dd, J=8.2 Hz, 1H), 7.10-7.04 (m, 2H), 6.91 (dd, J=1.6, 8.2 Hz, 1H),5.18 (s, 2H), 3.94 (s, 3H), 3.82 (s, 3H). [M+H]=312.28.

Example 2221-{[6-Methoxy-5-(3-methylphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine

¹H NMR (400 MHz, CD₃OD) δ 8.12 (m, 2H), 7.64-7.29 (m, 4H), 7.16 (br s,1H), 5.17 (br s, 2H), 3.94 (s, 3H), 2.37 (s, 3H). [M+H]=296.29.

Example 2233-{5-[(3-Amino-1H-1,2,4-triazol-1-yl)methyl]-2-methoxypyridin-3-yl}benzonitrile

¹H NMR (400 MHz, CD₃OD) δ 8.19 (br s, 1H), 8.13 (br s, 1H), 7.92-7.68(m, 4H), 7.61 (d, J=7.8 Hz, 1H), 5.19 (br s, 2H), 3.96 (s, 3H).[M+H]=307.26.

Example 2241-{[5-(3-Ethoxyphenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine

¹H NMR (400 MHz, CD₃OD) δ 8.13-8.09 (m, 2H), 7.66 (d, J=2.3 Hz, 1H),7.31-7.25 (m, 1H), 7.07-7.03 (m, 2H), 6.91-6.87 (m, 1H), 5.17 (s, 2H),4.05 (d, J=7.0 Hz, 2H), 3.93 (s, 3H), 1.39 (t, J=7.0 Hz, 3H).[M+H]=326.26.

Example 2251-{[5-(3-Cyclopropoxyphenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine

¹H NMR (400 MHz, CD₃OD) δ 8.16-8.09 (m, 2H), 7.66 (d, J=2.38 Hz, 1H),7.36-7.16 (m, 2H), 7.11-7.02 (m, 2H), 5.18 (s, 2H), 3.94 (s, 3H), 3.80(tt, J=6.01, 2.96 Hz, 1H), 0.82-0.67 (m, 4H). [M+H]=338.27.

Example 2261-({5-[3-(Difluoromethoxy)phenyl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-amine

¹H NMR (400 MHz, CD₃OD) δ 8.18-8.07 (m, 2H), 7.71 (d, J=2.3 Hz, 1H),7.50-7.34 (m, 3H), 7.17-7.09 (m, 1H), 7.06-6.62 (m, 1H), 5.18 (s, 2H),4.41 (q, J=7.0 Hz, 2H), 1.35 (t, J=7.0 Hz, 3H). [M+H]=362.24.

Example 2271-{[6-(Difluoromethoxy)-5-(3-methoxyphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine

¹H NMR (400 MHz, CD₃OD) δ 8.22-8.11 (m, 2H), 7.84 (d, J=2.3 Hz, 1H),7.80-7.39 (m, 1H), 7.35 (t, J=8.0 Hz, 1H), 7.10-7.05 (m, 2H), 6.97 (dd,J=2.5, 8.4 Hz, 1H), 5.24 (s, 2H), 3.82 (s, 3H). [M+H]=348.22.

Example 2281-{[5-(5-Chloropyridin-3-yl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine

¹H NMR (400 MHz, CD₃OD) δ 9.28 (s, 1H), 8.78 (d, J=1.76 Hz, 1H), 8.66(d, J=2.13 Hz, 1H), 8.38 (d, J=2.26 Hz, 1H), 8.31 (t, J=2.01 Hz, 1H),8.01 (d, J=2.26 Hz, 1H), 5.38 (s, 2H), 4.02 (s, 3H). [M+H]=317.21.

Example 2291-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-amine

¹H NMR (400 MHz, CD₃OD) δ 8.25-8.19 (m, 2H), 8.13 (s, 1H), 7.84 (d,J=2.3 Hz, 1H), 7.76-7.55 (m, 1H), 7.44-7.36 (m, 1H), 7.18 (d, J=0.8 Hz,1H), 5.19 (s, 2H), 3.98 (s, 3H). [M+H]=349.25.

Example 2301-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-amine

¹H NMR (400 MHz, CD₃OD) δ 8.24 (dd, J=0.8, 5.1 Hz, 1H), 8.21 (d, J=2.3Hz, 1H), 8.14 (s, 1H), 7.85 (d, J=2.7 Hz, 1H), 7.77-7.57 (m, 1H), 7.43(dd, J=1.6, 5.5 Hz, 1H), 7.22 (dd, J=0.8, 1.6 Hz, 1H), 5.20 (s, 2H),4.47 (q, J=7.0 Hz, 2H), 1.37 (t, J=7.0 Hz, 3H). [M+H]=363.19.

Example 2311-{[6-(Difluoromethoxy)-5-[2-(difluoromethoxy)pyridin-4-yl]pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine

¹H NMR (400 MHz, CD₃OD) δ 8.32-8.27 (m, 2H), 8.16 (s, 1H), 7.99 (d,J=2.3 Hz, 1H), 7.84-7.38 (m, 3H), 7.19-7.16 (m, 1H), 5.27 (s, 2H).[M+H]=385.20.

Example 2321-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-pyrazol-3-amine

¹H NMR (400 MHz, CD₃OD) δ 8.04 (d, J=2.3 Hz, 1H), 7.58 (d, J=2.3 Hz,1H), 7.46-7.30 (m, 4H), 7.14-7.09 (m, 1H), 7.02-6.64 (m, 1H), 5.64 (d,J=2.3 Hz, 1H), 5.10 (s, 2H), 3.93 (s, 3H). [M+H]=347.37.

Example 2331-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-pyrazol-5-amine

¹H NMR (400 MHz, CD₃OD) δ 7.99 (d, J=2.3 Hz, 1H), 7.55 (d, J=2.7 Hz,1H), 7.44-7.33 (m, 2H), 7.30 (t, J=2.0 Hz, 1H), 7.22 (d, J=2.0 Hz, 1H),7.13-7.09 (m, 1H), 7.02-6.63 (m, 1H), 5.50 (d, J=2.3 Hz, 1H), 5.16 (s,2H), 3.92 (s, 3H). [M+H]=347.37.

Example 2344-Chloro-1-{[5-(3-chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazol-3-amine

¹H NMR (400 MHz, CD₃OD) δ 8.05 (d, J=2.7 Hz, 1H), 7.62 (d, J=2.3 Hz,1H), 7.59-7.56 (m, 2H), 7.48-7.44 (m, 1H), 7.41-7.32 (m, 2H), 5.06 (s,2H), 4.40 (q, J=7.0 Hz, 2H), 1.38-1.30 (t, J=7.0 Hz, 3H). [M+H]=363.30.

Example 2354-Chloro-1-{[5-(3-chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazol-5-amine

¹H NMR (400 MHz, CD₃OD) δ 7.99 (d, J=2.3 Hz, 1H), 7.60-7.55 (m, 2H),7.47-7.43 (m, 1H), 7.41-7.32 (m, 2H), 7.25 (s, 1H), 5.16 (s, 2H), 4.39(q, J=7.4 Hz, 2H), 1.34 (t, J=7.0 Hz, 4H). [M+H]=363.30.

Example 2361-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-pyrazol-4-amine

The title compound was prepared in a manner analogous to Example 217,two products were formed. ¹H NMR (400 MHz, CD₃OD) δ 8.14 (s, 1H), 8.07(s, 1H), 8.03 (s, 1H), 7.98 (d, J=4.30 Hz, 1H), 7.61 (s, 1H), 7.47-7.39(m, 2H), 5.49 (s, 2H), 4.06 (s, 3H). [M+H]=316.10.

Example 2371-((6-(3-(Difluoromethoxy)phenyl)-5-ethoxypyrazin-2-yl)methyl)-1H-1,2,4-triazol-3-amine

¹H NMR (400 MHz, CD₃OD) δ 8.64-8.50 (m, 1H), 8.18 (s, 1H), 7.93 (td,J=1.4, 7.8 Hz, 1H), 7.86 (t, J=2.0 Hz, 1H), 7.46 (t, J=8.0 Hz, 1H), 7.20(dd, J=2.0, 8.2 Hz, 1H), 7.05-6.60 (m, 1H), 5.52 (s, 2H), 4.51 (q, J=7.3Hz, 2H), 1.44 (t, J=7.0 Hz, 3H). [M+H]=363.14.

Example 2381-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-N-methyl1H-1,2,4-triazol-3-amine

To a solution of1-((5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)methyl)-1H-1,2,4-triazol-3-amine(Example 219, 120 mg, 0.34 mmol) in DCM (2 mL), was added formaldehyde(26 μL of 37 wt % solution, 0.35 mmol), sodium triacetoxyborohydride(145 mg, 0.68 mmol) and a few drops of AcOH. The mixture was stirred atroom temperature for 16 h. Purification by reverse-phase PREP-HPLC gavethe title compound (25 mg, 20%). ¹H NMR (400 MHz, CD₃OD) δ 8.19-8.11 (m,1H), 7.82 (d, J=2.0 Hz, 1H), 7.71 (s, 1H), 7.53 (s, 1H), 7.47 (s, 1H),7.41-7.28 (m, 3H), 5.21 (s, 2H), 2.72 (s, 3H). [M+H]=366.21.

Example 2391-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-N,N-dimethyl-1H-1,2,4-triazol-3-amine

Prepared as a product of the reaction from procedure as Example 238.Purification by reverse-phase PREP-HPLC gave the title compound (41 mg,32%). ¹H NMR (400 MHz, CD₃OD) δ 8.57 (s, 1H), 8.25 (d, J=2.0 Hz, 1H),7.93 (d, J=2.3 Hz, 1H), 7.84-7.61 (m, 1H), 7.57 (s, 1H), 7.50-7.39 (m,3H), 5.32 (s, 2H), 2.96 (s, 6H). [M+H]=380.24.

Example 240(1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanamine

To a cooled solution, −78° C., of1-((5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carbonitrile(Example 156, 345 mg, 0.95 mmol) in DCM (5 mL) was slowly addeddiisobutylaluminum hydride (135.64 mg, 0.95 mmol). The mixture wasstirred at −78° C. for 1 h. The reaction was quenched with wet sodiumsulphate and stirred at room temperature for 30 min. The white aluminumprecipitate was filtered and the filtrate concentrated under reducedpressure. Purification (FCC, SiO₂, 40-100% EtOAc/DCM, followed by 0-10%MeOH/DCM) afforded the title compound (37 mg, 10%). ¹H NMR (400 MHz,CD₃OD) δ 8.54 (s, 1H), 8.25 (d, J=2.3 Hz, 1H), 7.92 (d, J=2.3 Hz, 1H),7.81-7.40 (m, 5H), 5.45 (s, 2H), 3.85-3.82 (m, 2H). [M+H]=366.20.

Example 2411-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazole-3-carboxamide

To a solution of methyl1-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carboxylate(Example 141, 103 mg, 0.28 mmol) in methanol (2 mL) was added ammonia inmethanol (2 mL of 7N solution, 14 mmol). The mixture was heated usingmicrowave irradiation at 130° C. for 20 min. The LCMS showed incompleteconversion. To the reaction mixture was added more ammonia in methanol(2 mL, 14 mmol) and irradiated in a microwave at 120° C. for anadditional 20 min. The solvent was removed under reduced pressure.Purification (FCC, SiO₂, 0-5% MeOH/DCM) afforded the title compound (77mg, 77%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.74 (s, 1H), 8.25 (d, J=2.3 Hz,1H), 7.85 (d, J=2.3 Hz, 1H), 7.78-7.70 (m, 1H), 7.62-7.40 (m, 5H), 5.45(s, 2H), 3.87 (s, 3H). [M+H]=354.18.

Example 2422-Methoxy-3-(1H-pyrazol-4-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine

The title compound was prepared in a manner analogous to Example 4, fromIntermediate 13 and the appropriate pyrazole boronic acid. ¹H NMR (400MHz, DMSO-d₆) δ 8.69 (s, 1H), 8.07 (s, 1H), 8.01 (q, J=2.3 Hz, 2H), 7.99(s, 1H), 5.37 (s, 1H), 3.94 (s, 3H), 2.52 (s, 1H). [M+H]=257.26.

Examples 243-246 were prepared in a manner analogous to Example 90, withthe appropriate starting materials and reagent substitutions.

Example 2434-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N-(oxetan-3-yl)benzamide

¹H NMR (400 MHz, CD₃OD) δ 7.94 (d, J=2.3 Hz, 1H), 7.71 (d, J=8.2 Hz,2H), 7.47-7.39 (m, 2H), 7.34-7.19 (m, 5H), 5.07-4.97 (m, 1H), 4.81 (d,J=7.4 Hz, 2H), 4.60 (t, J=6.5 Hz, 2H), 3.94 (s, 2H), 3.83 (s, 3H).[M+H]=409.24.

Example 2445-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-N-methylpyridine-2-carboxamide

The title compound was prepared in a manner analogous to Example 90 withthe appropriate starting material substitutions. ¹H NMR (400 MHz, CD₃OD)δ 8.57 (d, J=1.6 Hz, 1H), 8.14 (d, J=2.0 Hz, 1H), 8.01 (d, J=7.8 Hz,1H), 7.83 (dd, J=2.0, 8.2 Hz, 1H), 7.78 (d, J=2.3 Hz, 1H), 7.59 (s, 1H),7.54 (s, 1H), 7.47-7.38 (m, 3H), 4.15 (s, 2H), 2.94 (s, 3H).[M+H]=404.17.

Example 2451-(4-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}phenyl)cyclopropane-1-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.10 (d, J=2.35 Hz, 1H), 7.76 (s, 1H), 7.73(d, J=2.35 Hz, 1H), 7.58 (s, 1H), 7.53-7.49 (m, 1H), 7.46-7.30 (m, 4H),7.30-7.21 (m, 2H), 4.04 (s, 2H), 1.47 (q, J=3.65 Hz, 1H), 1.09-1.00 (m,2H) 0.90-0.80 (m, 2H). [M+H]=429.10.

Example 2462-(4-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}phenyl)acetamide

¹H NMR (400 MHz, CD₃OD) δ 8.08 (d, J=2.35 Hz, 1H), 7.76 (s, 1H), 7.67(d, J=2.35 Hz, 1H), 7.57 (s, 1H), 7.50 (m, 1H), 7.34-7.44 (m, 2H),7.17-7.28 (m, 4H), 4.01 (s, 2H), 3.47 (s, 2H). [M+H]=403.29.

Example 2472-(1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)propan-2-ol

To a solution of1-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carboxylate(Example 141, 104 mg, 0.28 mmol) in DCM (2 mL) was added methylmagnesiumbromide in diethyl ether (0.28 mL of 3M solution, 0.84 mmol). Themixture was stirred at room temperature for 20 min. The mixture wascarefully quenched with wet sodium sulfate, diluted with DCM, filteredand concentrated under reduced pressure. Purification (FCC, SiO₂,50-100% EtOAc/hexanes) afforded the title compound (67 mg, 67%). ¹H NMR(400 MHz, CDCl₃) δ 8.15 (d, J=2.0 Hz, 1H), 8.00 (s, 1H), 7.59-7.48 (m,2H), 7.42-7.31 (m, 3H), 5.28 (s, 2H), 3.98 (s, 3H), 3.70 (s, 1H), 1.62(s, 6H). [M+H]=359.09.

Example 2482-Methoxy-3-(1-methyl-1H-pyrazol-4-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine

The title compound was prepared in a manner analogous to Example 4, fromIntermediate 13 and the appropriate pyrazole boronic acid. (400 MHz,DMSO-_(d6)) δ 8.67 (s, 1H), 8.14 (s, 1H), 8.01 (d, J=2.0 Hz, 1H), 7.98(d, J=2.7 Hz, 2H), 7.90 (s, 1H), 5.37 (s, 2H), 3.94 (s, 3H), 3.86 (s,3H). [M+H]=271.15.

Examples 249-252 were prepared in a manner analogous to Example 247,with the appropriate starting materials and reagent substitutions.

Example 2492-(1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-5-yl)propan-2-ol

¹H NMR (400 MHz, CDCl₃) δ 8.15 (d, J=2.0 Hz, 1H), 7.79 (s, 1H), 7.64 (d,J=2.0 Hz, 1H), 7.51 (s, 1H), 7.41-7.29 (m, 3H), 5.63 (s, 2H), 3.96 (s,3H), 2.11 (s, 1H), 1.70 (s, 6H). [M+H]=359.09.

Example 2502-(4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)propan-2-ol

¹H NMR (400 MHz, CD₃OD) δ 7.99 (d, J=2.0 Hz, 1H), 7.49 (d, J=1.6 Hz,2H), 7.45-7.27 (m, 5H), 7.19 (d, J=8.2 Hz, 2H), 3.94 (s, 2H), 3.65 (s,3H), 1.50 (s, 6H). [M+H]=368.23.

Example 2512-(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridin-2-yl)propan-2-ol

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 8.04 (d, J=2.0 Hz, 1H),7.70-7.58 (m, 2H), 7.57-7.48 (m, 2H), 7.43-7.28 (m, 3H), 3.99 (s, 2H),3.92 (s, 3H), 1.51 (s, 6H). [M+H]=369.23.

Example 2522-(5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridin-2-yl)propan-2-ol

¹H NMR (400 MHz, CD₃OD) δ 8.41 (d, J=2.0 Hz, 1H), 8.12 (d, J=2.3 Hz,1H), 7.78-7.57 (m, 4H), 7.52 (d, J=1.6 Hz, 1H), 7.46-7.36 (m, 3H), 4.07(s, 2H), 1.51 (s, 6H). [M+H]=405.22.

Example 2533-[3-(Difluoromethoxy)phenyl]-5-{[3-(fluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}-2-methoxypyridine

To a solution of(1-((5-(3-(difluoromethoxy)phenyl)-6-methoxypyridin-3-yl)methyl)-1H-1,2,4-triazol-3-yl)methanol(Example 202, 40.0 mg, 0.11 mmol) in DCM (3 mL) was added Deoxo-Fluor®(36.64 mg, 0.17 mmol). The mixture was stirred at room temperature for 2h. The material was adsorbed on silica and purified (FCC, SiO₂, 20-100%EtOAc/hexanes) to afford the title compound (11 mg, 27%). ¹H NMR (400MHz, CD₃OD) δ 8.61 (s, 1H), 8.21 (d, J=2.3 Hz, 1H), 7.77 (d, J=2.3 Hz,1H), 7.49-7.36 (m, 2H), 7.33 (t, J=2.2 Hz, 1H), 7.16-7.11 (m, 1H),7.04-6.65 (m, 1H), 5.44 (s, 2H), 5.41-5.28 (m, 2H), 3.96 (s, 3H).[M+H]=365.21.

Examples 254-258 were prepared in a manner analogous to Example 253,with the appropriate starting materials and reagent substitutions.

Example 2543-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[4-(fluoromethyl)-1H-1,2,3-triazol-1-yl]methyl}pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.23-8.18 (m, 2H), 7.76 (d, J=2.3 Hz, 1H),7.48-7.36 (m, 3H), 7.17-7.11 (m, 1H), 7.03-6.65 (m, 1H), 5.64 (s, 2H),5.42 (d, J=48 Hz, 2H), 4.42 (q, J=7.0 Hz, 2H), 1.35 (t, J=7.2 Hz, 3H).[M+H]=379.23.

Example 2552-(Difluoromethoxy)-3-(3-ethoxyphenyl)-5-{[3-(fluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.63 (s, 1H), 8.23 (d, J=2.3 Hz, 1H), 7.90 (d,J=2.3 Hz, 1H), 7.81-7.42 (m, 1H), 7.38-7.31 (m, 1H), 7.10-7.03 (m, 2H),6.96 (ddd, J=1.0, 2.5, 8.2 Hz, 1H), 5.53-5.27 (m, 4H), 4.16-4.00 (q,J=7.0 Hz, 2H), 1.47-1.35 (t, J=7.0 Hz, 3H). [M+H]=379.27.

Example 2563-[2-(Difluoromethoxy)pyridin-4-yl]-5-{[3-(fluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}-2-methoxypyridine

¹H NMR (400 MHz, CD₃OD) δ 8.61 (s, 1H), 8.29 (d, J=2.3 Hz, 1H),8.26-8.21 (m, 1H), 7.90 (d, J=2.3 Hz, 1H), 7.76-7.39 (m, 2H), 7.19 (dd,J=0.8, 1.6 Hz, 1H), 5.48-5.27 (m, 4H), 4.00 (s, 3H). [M+H]=366.23.

Example 2573-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[3-(fluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyrazine

¹H NMR (400 MHz, CD₃OD) δ 8.77-8.66 (m, 1H), 8.24 (s, 1H), 8.03-7.92 (m,1H), 7.87 (d, J=10.6 Hz, 1H), 7.57-7.41 (m, 1H), 7.25 (dd, J=2.7, 8.2Hz, 1H), 7.17-6.71 (m, 1H), 5.61 (s, 2H), 5.58-5.54 (m, 1H), 5.45-5.29(m, 1H), 4.61-4.47 (m, 2H), 1.52-1.43 (m, 3H). [M+H]=380.13.

Example 2583-(3-Chlorophenyl)-5-{[3-(fluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}-2-methoxypyrazine

¹H NMR (400 MHz, DMSO-d₆) δ 8.76 (s, 1H), 8.31 (s, 1H), 8.00-7.86 (m,2H), 7.58-7.45 (m, 2H), 5.58 (s, 2H), 5.38 (s, 1H), 5.26 (s, 1H), 3.99(s, 3H). [M+H]=334.16.

Example 2593-(3-Chlorophenyl)-2-(difluoromethoxy)-5-{[3-(difluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine

Step 1. Methyl1-((5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carboxylate.The title compound was prepared in a manner analogous to Example 127with the appropriate starting material substitutions.

Step 2.1-((5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carbaldehyde.To a cooled solution, −78° C., of methyl1-((5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carboxylate(146 mg, 0.37 mmol) in DCM (5 mL) was added diisobutylaluminum hydride(52.6 mg, 0.37 mmol) slowly. The mixture was stirred at −78° C. for 1 h.The reaction was quenched with wet sodium sulphate and stirred at roomtemperature for 30 min. The white aluminum salt precipitate obtained wasfiltered and (the filtrate) concentrated under reduced pressure. Thecrude product was purified (FCC, SiO₂, 40-100% EtOAc/DCM followed by0-5% MeOH/DCM) to afford the title compound (69 mg; 51%).

Step 3.3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-{[3-(difluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine.To a solution of45-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carbaldehyde(69 mg, 0.19 mmol) in DCM (5 mL) was added Deoxo-Fluor® (104.6 mg, 0.47mmol). The mixture was stirred at room temperature for 16 h. The LCMSsuggested the presence of the title compound. The material was adsorbedon silica and purified (FCC, SiO₂, 10-100% EtOAc/hexanes) to afford thetitle compound (13 mg, 18%). ¹H NMR (400 MHz, CD₃OD) δ 8.69 (s, 1H),8.28 (d, J=2.3 Hz, 1H), 7.95 (d, J=2.3 Hz, 1H), 7.81-7.39 (m, 5H),6.94-6.65 (m, 1H), 5.54 (s, 2H). [M+H]=387.17.

Examples 260-261 were prepared in a manner analogous to Example 259,with the appropriate starting materials and reagent substitutions.

Example 2603-[3-(Difluoromethoxy)phenyl]-5-{[3-(difluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}-2-ethoxypyridine

¹H NMR (400 MHz, CD₃OD) δ 8.67 (s, 1H), 8.20 (d, J=2.3 Hz, 1H), 7.79 (d,J=2.3 Hz, 1H), 7.51-7.35 (m, 3H), 7.18-7.10 (m, 1H), 7.04-6.63 (m, 2H),5.47 (s, 2H), 4.42 (q, J=7.0 Hz, 2H), 1.35 (t, J=7.0 Hz, 3H).[M+H]=397.24.

Example 2613-[2-(Difluoromethoxy)pyridin-4-yl]-5-{[3-(difluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}-2-methoxypyridine

¹H NMR (400 MHz, CD₃OD) δ 8.67 (s, 1H), 8.30 (d, J=2.3 Hz, 1H), 8.23 (d,J=5.1 Hz, 1H), 7.92 (d, J=2.3 Hz, 1H), 7.77-7.55 (m, 1H), 7.41-7.39 (m,1H), 7.21-7.17 (m, 1H), 6.95-6.63 (m, 1H), 5.49 (s, 2H), 3.99 (s, 3H).[M+H]=384.21.

Example 2623-(3-Chlorophenyl)-2-methoxy-5-(1H-1,2,3-triazol-1-ylmethyl)pyridine

Step 1. 5-(Azidomethyl)-3-(3-chlorophenyl)-2-methoxypyridine. To asolution of 5-(bromomethyl)-3-(3-chlorophenyl)-2-methoxypyridine(Intermediate 2, 160 mg, 0.51 mmol) in DMF (5 mL) was added sodium azide(0.05 g, 0.77 mmol) and potassium carbonate (0.14 g, 1.02 mmol). Themixture was stirred at room temperature for 16 h. The mixture wasdiluted with a saturated aqueous solution of sodium chloride andextracted into diethyl ether. All solvents were removed under reducedpressure to affore the title compound, which was used in the next stepwithout further purification.

Step 2.3-(3-Chlorophenyl)-2-methoxy-5-((4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)methyl)pyridine.To a solution of 5-(azidomethyl)-3-(3-chlorophenyl)-2-methoxypyridine(directly used from previous reaction) and ethynyltrimethylsilane (75.1mg, 0.77 mmol) in THF (3 mL), water (1 mL), was added copper (I) iodide(19.4 mg, 0.10 mmol) and diisopropylethylamine (132 mg, 1.02 mmol). Themixture was stirred at room temperature for 2 h. The mixture was dilutedwith water and extracted in to DCM. The organic layers were combined,dried (Na₂SO₄), filtered and concentrated under reduced pressure.Purification (FCC, SiO₂, 0-50% EtOAc/hexanes) afforded the titlecompound (92 mg, 48%). [M+H]=373.2.

Step 3.3-(3-Chlorophenyl)-2-methoxy-5-(1H-1,2,3-triazol-1-ylmethyl)pyridine. Toa solution of3-(3-chlorophenyl)-2-methoxy-5-((4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)methyl)pyridine(92.0 mg, 0.25 mmol) in THF (3 mL) was added tetrabutylammonium fluoride(129 mg, 0.49 mmol). The mixture was stirred at room temperature for 16h. The mixture was diluted with water and extracted in to DCM. The DCMextracts were combined, dried (Na₂SO₄), filtered and concentrated underreduced pressure. Purification (FCC, SiO₂, 0-80% EtOAc/DCM) afforded thetitle compound (44 mg, 59%). ¹H NMR (400 MHz, CD₃OD) δ 8.10 (br s, 1H),7.95 (s, 1H), 7.65-7.59 (m, 2H), 7.42 (br s, 1H), 7.35-7.21 (m, 3H),5.54 (s, 2H), 3.85 (s, 3H). [M+H]=301.17.

Examples 263-268 were prepared in a manner analogous to Example 262,with the appropriate starting materials and reagent substitutions.

Example 263[1-({5-[3-(Difluoromethoxy)phenyl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,3-triazol-4-yl]methanol

¹H NMR (400 MHz, CD₃OD) δ 8.19 (d, J=2.7 Hz, 1H), 7.98 (s, 1H), 7.74 (d,J=2.3 Hz, 1H), 7.47-7.35 (m, 3H), 7.14 (dd, J=1.2, 2.0 Hz, 1H),7.03-6.64 (m, 1H), 5.60 (s, 2H), 4.73-4.60 (m, 2H), 4.41 (d, J=7.0 Hz,2H), 1.34 (t, J=7.0 Hz, 3H). [M+H]=377.25.

Example 264(1-((6-(Difluoromethoxy)-5-(3-ethoxyphenyl)pyridin-3-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol

¹H NMR (400 MHz, CD₃OD) δ 8.23 (d, J=2.3 Hz, 1H), 8.00 (s, 1H), 7.86 (d,J=2.3 Hz, 1H), 7.61 (t, J=1.0 Hz, 1H), 7.37-7.31 (m, 1H), 7.05 (ddd,J=1.2, 2.5, 3.7 Hz, 2H), 6.95 (ddd, J=1.0, 2.4, 8.3 Hz, 1H), 5.67 (s,2H), 4.66 (s, 2H), 4.07 (q, J=6.8 Hz, 2H), 1.40 (t, J=7.0 Hz, 3H).[M+H]=377.25.

Example 265[1-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)-1H-1,2,3-triazol-4-yl]methanol

¹H NMR (400 MHz, CD₃OD) δ 8.19 (s, 1H), 8.05 (s, 1H), 7.98-7.93 (m, 1H),7.88 (t, J=2.0 Hz, 1H), 7.47 (t, J=8.0 Hz, 1H), 7.21 (dd, J=3.5, 8.2 Hz,1H), 7.05-6.65 (m, 1H), 5.73 (s, 2H), 4.67 (s, 2H), 4.51 (q, J=7.0 Hz,2H), 1.44 (t, J=7.2 Hz, 3H). [M+H]=378.24.

Example 266(1-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-1,2,3-triazol-4-yl)methanol

¹H NMR (400 MHz, CD₃OD) δ 8.22 (s, 1H), 8.06-8.02 (m, 2H), 7.99 (ddd,J=1.6, 3.6, 5.4 Hz, 1H), 7.44-7.40 (m, 2H), 5.74 (s, 2H), 4.67 (s, 2H),4.06 (s, 3H). [M+H]=332.15.

Example 267[1-({6-[3-(Difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)-1H-1,2,3-triazol-4-yl]methanol

¹H NMR (400 MHz, DMSO-d₆) δ 8.31-8.29 (m, 1H), 8.05 (s, 1H), 7.88-7.84(m, 1H), 7.76-7.72 (m, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.45-7.05 (m, 2H),5.72 (s, 2H), 5.16-5.05 (m, 1H), 4.49 (d, J=5.1 Hz, 2H), 3.98 (s, 3H).[M+H]=364.24.

Example 268(1-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-1H-1,2,3-triazol-4-yl)methanol

¹H NMR (400 MHz, DMSO-d₆) δ 8.28 (s, 1H), 8.05 (s, 1H), 8.03-8.00 (m,1H), 7.99-7.94 (m, 1H), 7.53-7.49 (m, 2H), 5.71 (s, 2H), 5.16-5.08 (m,1H), 4.50-4.41 (m, 4H), 1.39-1.32 (m, 3H). [M+H]=346.18.

Example 2693-[3-(Difluoromethoxy)phenyl]-5-{[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]methyl}-2-ethoxypyridine

Step 1.1-((5-(3-(Difluoromethoxy)phenyl)-6-ethoxypyridin-3-yl)methyl)-1H-1,2,3-triazole-4-carbaldehyde.To a solution of[1-({5-[3-(difluoromethoxy)phenyl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,3-triazol-4-yl]methanol(Example 263, 115 mg, 0.31 mmol), in DCM (5 mL) was added Dess-MartinReagent® (1.22 mL, 0.30 mol/L, 0.37 mmol). The reaction mixture wasallowed to stir at room temperature for 3 hr. The reaction was quenchedwith wet sodium sulphate. The reaction mixture was extracted into DCM,filtered and solvent removed under reduced pressure. Purification (FCC,SiO₂, 10-100% EtOAc/hexanes) afforded the title compound (90 mg, 79%).

Step 2.3-[3-(Difluoromethoxy)phenyl]-5-{[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]methyl}-2-ethoxypyridine.To a solution of1-((5-(3-(difluoromethoxy)phenyl)-6-ethoxypyridin-3-yl)methyl)-1H-1,2,3-triazole-4-carbaldehyde(90 mg, 0.24 mmol) in DCM (5 mL) was added Deoxo-Fluor® (133 mg, 0.60mmol). The mixture was stirred at room temperature for 4 h. The materialwas adsorbed on silica. Purification (FCC, SiO₂, 0-80% EtOAc/hexanes)afforded the title compound (53 mg, 56%). ¹H NMR (400 MHz, CD₃OD) δ 8.36(t, J=1.4 Hz, 1H), 8.20 (d, J=2.3 Hz, 1H), 7.77 (d, J=2.7 Hz, 1H),7.47-7.36 (m, 3H), 7.16-7.10 (m, 1H), 7.07-6.63 (m, 2H), 5.66 (s, 2H),4.41 (q, J=7.0 Hz, 2H), 1.34 (t, J=7.2 Hz, 3H). [M+H]=397.24.

Example 2701-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-4-carboxylicacid

To a solution of ethyl1-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)-1H-pyrazole-4-carboxylate(Example 169, 25.00 mg, 0.07 mmol) in THF (2 mL), methanol (2 mL) wasadded lithium hydroxide (1.00 mL, 1.00 mol/L, 1.00 mmol). The mixturewas stirred at room temperature for 2 h. The solvents were removed underreduced pressure and the crude residue dissolved in water. The aqueousreaction mixture was acidified with 1 N HCl (5 mL), and extracted intoethyl acetate. The combined organic layers were dried (Na₂SO₄), filteredand concentrated under reduced pressure to afford the title compound (20mg, 87%). ¹H NMR (400 MHz, DMSO-d₆) δ 12.30 (br s, 1H), 8.39 (br s, 1H),8.19 (br s, 1H), 7.80 (br s, 2H), 7.68-7.26 (m, 4H), 5.34 (br s, 2H),3.87 (br s, 3H). [M+H]=344.31.

Example 2711-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-4-carboxamide

A solution of1-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)-1H-pyrazole-4-carbonitrile(Example 170, 25.00 mg, 0.08 mmol) in MeOH (1.54 mL) was heated to 50°C., until the starting material dissolved. Sodium hydroxide (0.23 mL,1.00 mol/L, 0.23 mmol) and hydrogen peroxide (0.23 mL, 1.00 mol/L, 0.23mmol) were added and the reaction stirred at 50° C. for 2 h. Water wasadded (5 mL), and the mixture was filtered and washed with water (3×5mL) to afford the title compound as a solid (25.0 mg, 95%). ¹H NMR (400MHz, DMSO-d₆) δ 8.20 (d, J=13.69 Hz, 2H), 7.80 (d, J=14.48 Hz, 2H),7.65-7.37 (m, 5H), 6.95 (br s, 1H), 5.32 (br s, 2H), 3.87 (br s, 3H).[M+H]=343.33.

Example 272[1-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-pyrazol-4-yl]methanol

Step 1.1-((5-(3-(Difluoromethoxy)phenyl)-6-methoxypyridin-3-yl)methyl)-1H-pyrazole-4-carbaldehyde.The title compound was prepared in a manner analogous to Example 127,with the appropriate starting material substitutions.

Step 2.[1-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-pyrazol-4-yl]methanol.To a solution of1-((5-(3-(difluoromethoxy)phenyl)-6-methoxypyridin-3-yl)methyl)-1H-pyrazole-4-carbaldehyde(99 mg, 0.27 mmol) in methanol (5 mL) was added sodium borohydride (14.3mg, 0.38 mmol). The mixture was stirred at room temperature for 10 min.The mixture was quenched with water (0.5 mL), diluted with DCM (10 mL),dried (Na₂SO₄), filtered and concentrated under reduced pressure.Purification (FCC, SiO₂, 20-100% EtOAc/hexanes) afforded the titlecompound (100 mg, 100%). ¹H NMR (400 MHz, CD₃OD) δ 8.10 (d, J=2.3 Hz,1H), 7.74-7.70 (m, 1H), 7.63 (d, J=2.3 Hz, 1H), 7.50 (s, 1H), 7.45-7.34(m, 2H), 7.30 (t, J=2.3 Hz, 1H), 7.13 (s, 1H), 7.03-6.64 (m, 1H), 5.31(s, 2H), 4.49 (s, 2H), 3.94 (s, 3H). [M+H]=362.21.

Examples 273-278 were prepared in a manner analogous to Example 272,with the appropriate starting materials and reagent substitutions.

Example 273(1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-imidazol-5-yl)methanol

¹H NMR (400 MHz, DMSO-d₆) δ 8.08-8.30 (m, 1H), 7.92 (d, J=2.35 Hz, 1H),7.77 (s, 1H), 7.57-7.62 (m, 1H), 7.43-7.54 (m, 3H), 6.81 (s, 1H), 5.27(s, 2H), 5.16 (t, J=5.28 Hz, 1H), 4.41 (d, J=5.09 Hz, 2H), 3.49-3.59 (m,2H). [M+H]=366.20.

Example 274(1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-imidazol-4-yl)methanol

¹H NMR (400 MHz, DMSO-d₆) δ 8.19-8.40 (m, 1H), 8.05 (d, J=2.35 Hz, 1H),7.83-7.46 (m, 6H), 7.13 (s, 1H), 5.20 (s, 2H), 4.28 (s, 2H), 3.55 (s,1H). [M+H]=366.20.

Example 275[1-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-pyrazol-3-yl]methanol

¹H (400 MHz, CD₃OD) δ 8.04 (d, J=2.3 Hz, 1H), 7.61 (d, J=2.3 Hz, 1H),7.47-7.27 (m, 4H), 7.13-7.08 (m, 1H), 7.03-6.63 (m, 1H), 6.29 (d, J=2.0Hz, 1H), 5.40 (s, 2H), 4.65 (s, 2H), 3.92 (s, 3H). [M+H]=362.17.

Example 276(1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazol-4-yl)methanol

¹H NMR (400 MHz, CD₃OD) δ 8.08 (d, J=2.3 Hz, 1H), 7.72 (s, 1H), 7.63 (d,J=2.3 Hz, 1H), 7.55 (t, J=1.6 Hz, 1H), 7.50 (s, 1H), 7.46-7.42 (m, 1H),7.40-7.31 (m, 2H), 5.30 (s, 2H), 4.49 (s, 2H), 4.39 (q, J=7.0 Hz, 2H),1.33 (t, J=7.0 Hz, 3H). [M+H]=344.33.

Example 277(4-Chloro-1-{[5-(3-chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazol-3-yl)methanol

¹H NMR (400 MHz, CD₃OD) δ 8.10 (d, J=2.3 Hz, 1H), 7.80 (s, 1H), 7.68 (d,J=2.3 Hz, 1H), 7.56 (s, 1H), 7.47-7.43 (m, 1H), 7.40-7.31 (m, 2H), 5.25(s, 2H), 4.53 (s, 2H), 4.39 (q, J=7.0 Hz, 2H), 1.33 (t, J=7.0 Hz, 3H).[M+H]=378.27.

Example 278(4-Chloro-1-{[5-(3-chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazol-5-yl)methanol

¹H NMR (400 MHz, CD₃OD) δ 8.08 (d, J=2.3 Hz, 1H), 7.68 (d, J=2.3 Hz,1H), 7.56 (s, 1H), 7.47 (s, 1H), 7.46-7.42 (m, 1H), 7.40-7.31 (m, 2H),5.40 (s, 2H), 4.67 (s, 2H), 4.40 (q, J=7.0 Hz, 2H), 1.33 (t, J=7.0 Hz,4H). [M+H]=378.27.

Example 2793-(4-Chloro-1H-pyrazol-1-yl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine

5-((1H-1,2,4-Triazol-1-yl)methyl)-3-(4-chloro-1H-Pyrazol-1-yl)-2-methoxypyridine.To a solution of5-((1H-1,2,4-triazol-1-yl)methyl)-3-Bromo-2-methoxypyridine(Intermediate 13), (100 mg, 0.37 mmol), in toluene (5 mL) was addedtris(dibenzylideneacetone)dipalladium(0) (34.1 mg, 0.04 mmol), sodiumtert-butoxide (71.6 mg, 0.74 mmol),(2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (29.3 mgs, 0.07mmol) and 4-chloro-1H-pyrazole (37.3 mg, 0.37 mmol). The mixture washeated at 100° C. for 30 min. The mixture was quenched with water (0.5mL), diluted with ethyl acetate (10 mL), dried (Na₂SO₄), filtered andconcentrated under reduced pressure. Purification (FCC, SiO₂, 20-100%EtOAc/hexanes) afforded the title compound (50 mg, 46%). ¹H NMR (400MHz, DMSO-d₆) δ 8.69 (s, 1H), 8.07 (s, 2H), 8.01 (q, J=2.3 Hz, 2H), 7.99(s, 1H), 5.37 (s, 2H), 3.94 (s, 3H), 2.52 (s, 1H). [M+H]=292.12.

Example 2804-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}benzoicacid

The title compound was prepared in a manner analogous to Example 21,with the appropriated starting material and reagent substitutions. ¹HNMR (400 MHz, CD₃OD) δ 8.01 (d, J=2.3 Hz, 1H), 7.87 (d, J=8.2 Hz, 2H),7.63 (d, J=2.3 Hz, 1H), 7.49 (s, 1H), 7.43 (s, 1H), 7.35-7.24 (m, 5H),4.01 (s, 2H). [M+H]=390.09.

PHARMACOLOGICAL EXAMPLES

The present disclosure will be further illustrated by the followingpharmacological examples. These examples are understood to be exemplaryonly and are not intended to limit the scope of the invention disclosedherein.

Enzymatic Assay

An IMAP TR-FRET based PDE assay was developed using the PDE4D3 isoform.IMAP technology is based on high-affinity binding of phosphate byimmobilized metal (MIII) coordination complexes on nanoparticles. TheIMAP “binding reagent” recognizes phosphate groups on AMP or GMPgenerated from cAMP or cGMP in a PDE reaction. The cyclic nucleotidesthat carry a phosphodiester bond and not a free phosphate are notrecognized by the binding reagent. The time resolved fluorescenceresonance energy transfer (TR-FRET) is afforded by a Terbium (Tb)-Donorprebound to the nanoparticles. FRET can occur when fluorescent-labeledAMP or GMP product of a PDE reaction binds comes into close proximity ofthe Tb-Donor complex. Due to the long lifetime of Tb fluorescence,detection can be run in time-resolved mode to eliminate interferencefrom autofluorescent compounds.

The IMAP TR-FRET PDE4D3 FAM-cAMP assay was performed in 1536-well whiteplates 15 pg per well GST-tagged PDE4D3 was dispensed in 2.5 μL IMAPassay buffer consisting of 10 mM Tris pH 7.2, 10 mM MgCl₂, 1 mM DTT,0.1% fatty acid free BSA and 0.01% Tween-20. 30 mL of compound was thenadded from 1 mM stock in DMSO using the Kalypsys 1536 10 mL pintool.Plates were incubated for 5 min at RT before dispensing 1.5 μL of 533 nMFAM-cAMP for a final concentration of 200 nM. Plates were incubated 30min at RT after a brief centrifugation. The assay was terminated byadding 5 μL IMAP binding reagent Tb complex to each well, preparedaccording to manufacturer's recommendations. Plates were incubated anadditional 90 minutes at RT and read on a Viewlux plate reader.Compounds were solvated at 10 mM in DMSO and tested in 11-pointdose-response in the PDE4D3 assay.

Pharmacological Example 1 PDE4 Inhibition

Representative compounds of the invention were evaluated in the PDE4enzymatic assay. Typically, the compounds of the invention show PDE4inhibitory properties at a concentration of 0.1 to 10 μM, typically at5-100%.

As depicted in the following Table, these inhibitory properties weremirrored by pEC₅₀ values ranging from less than 5 (10⁻⁵ M or 10 μM) togreater than 7 (10⁻⁷ M or 0.1 μM).

PD4d3 pEC₅₀ Example Numbers >7 1, 13, 25, 27, 28, 29, 30, 32, 33, 36,38, 40, 46, 47, 48, 55, 56, 58, 65, 66, 68, 69, 71, 72, 73, 76, 78, 79,80, 82, 84, 87, 89, 92, 93, 95, 100, 103, 104, 105, 106, 107, 110, 119,122, 123, 124, 125, 126, 131, 134, 143, 144, 145, 148, 151, 153, 155,162, 163, 165, 168, 173, 174, 183, 185, 201, 202, 203, 204, 205, 206,217, 219, 226, 229, 230, 232, 246, 253, 256, 260, 261, 262, 263, 264,272, 274, 275, 276 6-7 2, 5, 7, 12, 14, 20, 21, 24, 26, 34, 37, 41, 43,44, 45, 49, 51, 53, 57, 59, 60, 64, 67, 74, 75, 81, 83, 85, 86, 88, 90,91, 94, 96, 97, 102, 108, 109, 111, 112, 113, 114, 115, 116, 117, 118,120, 121, 128, 129, 130, 132, 136, 137, 139, 141, 142, 146, 147, 150,152, 154, 157, 159, 160, 161, 164, 166, 167, 170, 171, 176, 178, 179,180, 188, 189, 191, 200, 207, 208, 211, 212, 213, 214, 216, 218, 220,221, 222, 223, 224, 227, 231, 233, 234, 238, 239, 244, 245, 250, 251,252, 254, 255, 259, 265, 266, 267, 268, 269, 271, 277, 278 5-6 3, 8, 15,16, 17, 18, 19, 23, 31, 35, 39, 42, 50, 52, 54, 61, 62, 63, 70, 77, 98,99, 101, 127, 133, 135, 138, 149, 156, 158, 169, 172, 177, 181, 182,184, 186, 187, 190, 192, 193, 194, 195, 196, 197, 198, 199, 209, 210,215, 225, 228, 235, 237, 240, 241, 243, 247, 248, 257, 258, 273, 280 <54, 6, 9, 10, 11, 22, 140, 175, 236, 242, 249, 270, 279

BIOLOGICAL EXAMPLES

The present disclosure will be further illustrated by the followingbiological examples. These examples are understood to be exemplary onlyand are not intended to limit the scope of the invention disclosedherein.

Behavioral Assays

Numerous behavioral assays are available to assess the ability of acandidate compound to enhance memory formation, including contextualconditioning (e.g., fear conditioning), temporal conditioning (e.g.,trace conditioning), and object recognition. Other non-limiting examplesof appropriate assays to assess memory include those that incorporate orrelate to multiple training sessions, spaced training sessions,contextual fear training with single or multiple trials, trace fearconditioning with single or multiple trials, contextual memorygenerally, temporal memory, spatial memory, episodic memory, passiveavoidance memory, active avoidance memory, food preference memory,conditioned taste avoidance, and social recognition memory.

The behavioral assays can also be used in accordance with the presentinvention, as will be understood by those of ordinary skill in the art.These assays can be directed towards the evaluation of, withoutlimitation, hippocampus-, cortex, and/or amygdala-dependent memoryformation or cognitive performance.

Biological Example 1 Effect of PDE4 Inhibitors on Contextual MemoryRationale

Contextual fear conditioning is a form of associative learning in whichanimals learn to recognize a training environment (conditioned stimulus,CS) that has been previously paired with an aversive stimulus such asfoot shock (unconditioned stimulus, US). When exposed to the samecontext at a later time, conditioned animals show a variety ofconditional fear responses, including freezing behavior. The percent oftime during the test that the animal exhibits such freezing provides aquantitative measure of the contextual associative memory (e.g.,Fanselow, Behav. Neurosci. 1984, 98, 269-277; Fanselow, Behav. Neurosci.1984, 98, 79-95; and Phillips and LeDoux, Behav. Neurosci. 1992, 106,274-285).

Contextual conditioning has been extensively used to investigate theneural substrates mediating fear-motivated learning (e.g., Phillips andLeDoux, Behav. Neurosci. 1992, 106, 274-285; Kim et al., Behav.Neurosci. 1993, 107, 1093-1098; and Bourtchouladze et al., Learn. Mem.1998, 5, 365-374). Studies in mice and rats provided evidence forfunctional interaction between hippocampal and nonhippocampal systemsduring contextual conditioning training (e.g., Maren et al., Behav.Brain Res. 1997, 88, 261-274; Maren et al., Neurobiol. Learn. Mem. 1997,67, 142-149; and Frankland et al., Behav. Neurosci. 1998, 112, 863-874).Specifically, post-training lesions of the hippocampus (but notpre-training lesions) greatly reduced contextual fear, implying that: 1)the hippocampus is essential for contextual memory but not forcontextual learning per se and 2) in the absence of the hippocampusduring training, non-hippocampal systems can support contextualconditioning.

Contextual conditioning has been extensively used to study the impact ofvarious mutations on hippocampus-dependent learning, as well as strainand genetic background differences in mice (e.g., Bourtchouladze et al.,Cell 1994, 79, 59-68; Bourtchouladze et al., Learn Mem. 1998, 5,365-374; Kogan et al., Current Biology 1997, 7, 1-11; Silva et al.,Current Biology 1996, 6, 1509-1518; Abel et al., Cell 1997, 88, 615-626;Giese et al., Science 1998, 279, 870-873; Logue et al., Neuroscience1997, 80, 1075-1086; Chen et al., Behav. Neurosci. 1996, 110, 1177-1180;and Nguyen et al., Learn Mem. 2000, 7, 170-179).

Because robust learning can be triggered with a few minutes trainingsession, contextual conditioning has been especially useful to study thebiology of temporally distinct processes of short- and long-term memory(e.g., Kim et al., Behav. Neurosci. 1993, 107, 1093-1098; Bourtchouladzeet al., Cell 1994, 79, 59-68; Abel et al., Cell 1997, 88, 615-626; Logueet al., Behav. Neurosci. 1997, 111, 104-113; Bourtchouladze et al.,Learn. Mem. 1998, 5, 365-374; and Nguyen et al., Learn. Mem. 2000, 7,170-179). As such, contextual conditioning provides an excellent modelto evaluate the effects of novel drug compounds on hippocampal-dependentmemory formation.

Procedures

Previous investigations have established that training with 1× or2×CS-US pairings induces sub-maximal (weak) memory in wild-type mice(e.g., U.S.20090053140; Tully et al., Nat. Rev. Drug Discov. 2003, 2,267-77; and Bourtchouladze et al. Learn. Mem. 1998, 5, 365-374).Accordingly, contextual conditioning in this study was performed asdescribed by Bourtchouladze et al., Cell 1994, 79, 59-68.

Young-adult (10-12 weeks old) C57BL6 male mice and Sprague Dawley malerats were used. Mice and rats were group-housed in standard laboratoryand maintained on a 12:12 light-dark cycle. The experiments were alwaysconducted during the light phase of the cycle. With the exception oftesting times, the mice had ad libidum access to food and water. Toassess contextual memory, a modified contextual fear conditioning taskoriginally developed for evaluation of memory in CREB knock-out mice wasused (Bourtchouladze et al., 1994). Training sessions are comprised of abaseline period in the conditioning chamber (Med Associates, Inc.)followed by presentation of unconditioned stimuli (1-5 footshocks eachat 0.2-1.0 mA for 2-sec) spaced at 60-sec intervals. Thirty secondsfollowing the last shock, the animal is returned to the home cage. Oneto 7 days later, the animals are returned to the chamber and freezingbehavior is scored. Freezing (complete immobility except respiration) isscored by Video Freeze software (Med Associates, Inc.) over an 8 minutetest period. Treatment with cognition enhancers are expected tosignificantly increase freezing when compared with controls.

All experiments were designed and performed in a counterbalancedfashion. In each experiment, the experimenter was unaware (blind) to thetreatment of the subjects during training and testing. Training and testsessions were recorded as digital video files. Data were analyzed byone-way ANOVA with appropriate post-hoc tests using GraphPad Prismsoftware package.

Results

Exemplary compounds were found to enhance contextual memory in the fearconditioning assay. Significant enhancing effects are seen at severalconcentrations, including 0.01 mg/kg, 0.03 mg/kg, and 1.0 mg/kg.

Biological Example 2 Effect of PDE4 Inhibitors on Novel ObjectRecognition Rationale

Novel Object Recognition (NOR) is an assay of recognition learning andmemory retrieval, and it takes advantage of the spontaneous preferenceof rodents to investigate a novel object compared with a familiar one.It is an ethologically relevant task, which in contrast to fearconditioning, does not result from negative reinforcement (footshock)(e.g., Ennaceur and Delacour, Behav. Brain Res. 1988, 31, 47-59).

The NOR test has been employed extensively to assess the potentialcognitive-enhancing properties of novel compounds derived fromhigh-throughput screening. Object recognition the task relies on thenatural curiosity of rodents to explore novel objects in theirenvironments more than familiar ones. Obviously, for an object to be“familiar,” the animal must have attended to it before and rememberedthat experience. Hence, animals with better memory will attend andexplore a new object more than an object familiar to them. Duringtesting, the animal is presented with the training object and a second,novel one. Memory of the training object renders it familiar to theanimal, and it then spends more time exploring the new novel objectrather than the familiar one (Bourtchouladze et. al., Proc. Natl. Acad.Sci. USA 2003, 100, 10518-10522).

Neuroimaging, pharmacological, and lesion studies have demonstrated thatthe hippocampus and adjacent perirhinal cortex are critical for objectrecognition memory in rodents, monkeys, and humans (e.g., Mitchell,Behav. Brain Res. 1998, 97, 107-113; Teng et al., J. Neurosci. 2000, 20,3853-3863; Mumby, Brain Res. 2001, 127, 159-181; Eichenbaum et al.,Annu. Rev. Neurosci. 2007, 30, 127-152; Squire et al., Nat. Rev.Neurosci. 2007, 8, 872-883; and Vann and Alabasser, Curr. Opin.Neurobiol. 2011, 21, 440-445). Hence, object recognition provides anexcellent behavioral model to evaluate drug-compound effects oncognitive tasks associated with function of the hippocampus and cortex.

Procedures

Object recognition was tested in young adult mice and rats using thefollowing protocol. Animals are briefly handled by the experimenter 2-5days prior to training. Each compound was administered between 15minutes and 24-hours prior to, or following, training. Habituationsessions (duration 1-20 min, over 1-3 days) were conducted tofamiliarize the animal to the arena. During training trials (duration of1-20 min) the animals were allowed to explore two identical objects. Atest trial (duration of 1-20 min) was then performed 1-96 hrs later.

For novel object recognition, one object is replaced with one that isnovel. All combinations and locations of objects are used in a balancedmanner to reduce potential biases attributable to preference forparticular locations or objects. Training and test trials are recordedand scored by video-tracking software (e.g. Noldus Ethovision). Ananimal is scored as exploring an object when its head was orientedtoward the object within a distance of 1 cm (rat)₂ cm (mouse) or whenthe nose is touching the object. Turning around, climbing, or sitting onan object was not considered as exploration. If the animal generates along-term memory for the familiar object, it will spend significantlymore time exploring the novel object compared to the familiar objectduring the retention test (Cognitive enhancers are therefore expected tofacilitate this discrimination between the familiar and novel object).

A discrimination index was calculated as previously described(Bourtchouladze et al., Proc. Natl. Acad. Sci. USA 2003, 100,10518-10522). In each experiment, the experimenter was unaware (blind)to the treatment of the subjects during training and testing. Data wereanalyzed by one-way ANOVA with appropriate post-hoc tests using GraphPadPrism software package.

Results

Exemplary compounds of Formula (I) are found to significantly enhance 24hour memory. Significant effects were seen at several concentrations,including 1.0 mg/kg and 3 mg/kg.

The specification, including the examples, is intended to be exemplaryonly, and it will be apparent to those skilled in the art that variousmodifications and variations can be made in the present inventionwithout departing from the scope or spirit of the invention as definedby the appended claims.

Furthermore, while certain details in the present disclosure areprovided to convey a thorough understanding of the invention as definedby the appended claims, it will be apparent to those skilled in the artthat certain embodiments may be practiced without these details.Moreover, in certain instances, well-known methods, procedures, or otherspecific details have not been described to avoid unnecessarilyobscuring aspects of the invention defined by the appended claims.

What is claimed is:
 1. A chemical entity of Formula (I):

wherein: Z is CH; R¹ is a member selected from the group consisting of:—H, —C₁₋₃alkyl and —C₁₋₃haloalkyl; Y is —C(R^(a))₂—, where each R^(a) isindependently selected from the group consisting of: —H, —F, —CH₃, —OHand —N(R^(b))₂; R² is a member selected from the group consisting of: A)phenyl unsubstituted or substituted with one or two R^(c) members, whereeach R^(c) is independently selected from the group consisting of: halo,—CN, —CO₂R^(b), —CONH₂, —SO₂CH₃, —C(R^(b))₂OH, —CH₂NH₂, —CH₂CONH₂,—CH₂CO₂CH₃, —NHCONH₂, —NHCONH-oxetane, —CONH-oxetane,

B) six-membered monocyclic heteroaromatic ring containing one or twonitrogen members unsubstituted or substituted with one or two memberseach independently selected from the group consisting of: halo,—C₁₋₃alkyl, —C₁₋₃haloalkyl, —CN, —C(R^(b))₂OH, —CH₂NH₂, —OC₁₋₃ alkyl,—O—CH₂-cyclopropyl, —CO₂H, —CON(R^(b))₂, —N(R^(b))₂, —NHCH₂CF₃,—NHCH(CH₃)₂, —NHCH₂CH₂N(CH₃)₂, —NHcyclopropyl, and —NHCOCH₃; C)five-membered monocyclic heteroaromatic ring containing two or threenitrogen members unsubstituted or substituted with one or two memberseach independently selected from the group consisting of halo, —C₁₋₃alkyl, —C₁₋₃haloalkyl, —C(R^(b))₂OH, —N(R^(b))₂, —NO₂, —CN, —OC₁₋₃alkyl, —CH₂OCH₃, —CH₂NH₂, —CO₂C₁₋₃alkyl, —CO₂H, —CONH₂, —NHCOCH₃, andcyclopropyl; and D) five or six-membered heteroaromatic ring selectedfrom: 1,2-dihydro-pyridin-2-one, tetrazole, thiazole or oxazoleunsubstituted or substituted with one or two members each independentlyselected from the group consisting of —CH₃, and —NH₂; R³ is a memberselected from the group consisting of: phenyl, pyridyl, thiophene, andpyrazole, each substituted with a member selected from the groupconsisting of: halo, —C₁₋₃alkyl, —C₁₋₃haloalkyl, —OC₁₋₃ alkyl,—Ocyclopropyl, —OC₁₋₃haloalkyl, —CN, —CH₂OH and —SO₂CH₃; R⁴ is a memberselected from the group consisting of —C₁₋₃alkyl and —C₁₋₃haloalkyl; andeach R^(b) is independently selected from —H or —CH₃; wherein thechemical entity is selected from the group consisting of compounds ofFormula (I), and pharmaceutically acceptable salts of compounds ofFormula (I).
 2. A chemical entity as in claim 1, wherein R¹ is selectedfrom the group consisting of —H, —CH₃, and —CF₃.
 3. A chemical entity asin claim 1, wherein Y is selected from the group consisting of —CH₂—,—CH(F)—, —CH(OH)—, —C(OH)(CH₃)—, and —CH(CH₃)—.
 4. A chemical entity asin claim 1, wherein R² is

and R^(c) is a member selected from the group consisting of: —F, —CN,—CO₂H, —CONH₂, —SO₂CH₃, —C(CH₃)₂OH, —CH₂NH₂, —CH₂CONH₂, —CH₂CO₂CH₃,—NHCONH₂, —NHCONH-oxetane, —CONH-oxetane,


5. A chemical entity as in claim 1, wherein R² is

and R^(c) is selected from —F, —CONH₂, —CH₂CONH₂, —CH₂NH₂, —C(CH₃)₂OH,—SO₂CH₃, and —NHCONH₂.
 6. A chemical entity as in claim 1, wherein R² ispyridine, unsubstituted or substituted with one or two members eachindependently selected from the group consisting of —F, —C₁₋₃alkyl,—C₁₋₃haloalkyl, —OC₁₋₃alkyl, —OCH₂cyclopropyl, —CN, —N(R^(b))₂, —CH₂NH₂,—CO₂H, —CON(R^(b))₂, and —C(CH₃)₂OH.
 7. A chemical entity as in claim 1,wherein R² is

R^(d) is selected from the group consisting of: —CH₃, —CF₃, —CN,—N(R^(b))₂, —CO₂H, —CON(R^(b))₂, —OC₁₋₃alkyl, —CH₂NH₂, —C(CH₃)₂OH,—OCH₂cyclopropyl, and —OCH(CH₃)₂.
 8. A chemical entity as in claim 1,wherein R² is

unsubstituted or substituted with R^(d); where R^(d) is —CH₃, —CF₃,—NH₂, —NHCH₃, —N(CH₃)₂, —CONH₂, —CONHCH₃, —CON(CH₃)₂, —OC₁₋₃alkyl,—C(CH₃)₂OH, or —OCH₂cyclopropyl.
 9. A chemical entity as in claim 1,wherein R² is selected from the group consisting of pyrazine,6-methylpyridazin-3-amine and pyrimidine, where pyrimidine is optionallysubstituted with —Cl, —CH₃, —CN, —OC₁₋₃alkyl, —CO₂H, —CON(R^(b))₂,—C(CH₃)₂OH, —N(R^(b))₂, —NHCH₂CF₃, —NHCH(CH₃)₂, —CH₂CH₂N(CH₃)₂,—NHcyclopropyl, or —NHCOCH₃.
 10. A chemical entity as in claim 1,wherein R² is

unsubstituted or substituted with one or two R^(e) members, where eachR^(e) is independently —CH₃, —CN, —OCH₃, —CO₂H, —CONH₂, —C(CH₃)₂OH,—N(R^(b))₂, —NHCH₂CF₃, —NHCH(CH₃)₂, —CH₂CH₂N(CH₃)₂, —NHcyclopropyl, or—NHCOCH₃.
 11. A chemical entity as in claim 1, wherein R² is

unsubstituted or substituted with R^(e), where R^(e) is selected fromthe group consisting of: —CH₃, —CN, —OCH₃, —NH₂, —NHCH₃, —N(CH₃)₂,—NHCH₂CF₃, —NHcyclopropyl, —C(CH₃)₂OH, —CONH₂, —CONHCH₃, and —CON(CH₃)₂.12. A chemical entity as in claim 1, wherein R² is selected from thegroup consisting of imidazole, pyrazole, and triazole, unsubstituted orsubstituted with one or two members each independently selected from thegroup consisting of: —Cl, —CH₃, —CF₃, —CH₂OH, —NH₂, —NO₂, —CN,—CO₂C₁₋₃alkyl, —CO₂H, —CONH₂, and —NHCOCH₃.
 13. A chemical entity as inclaim 1, wherein R² is

and R^(f) is a member selected from the group consisting of: —H, —CH₃,—NO₂, —NH₂, —NHCOCH₃, —CH₂OH, —CN, —CONH₂, —CO₂H, and —CO₂CH₂CH₃.
 14. Achemical entity as in claim 1, wherein R² is

and R^(f) is a member selected from the group consisting of: —H, —NH₂,and —CH₂OH.
 15. A chemical entity as in claim 1, wherein R² is

where R^(g) is a member selected from the group consisting of: —H, —CH₃,—CH₂OH, and —NH₂.
 16. A chemical entity as in claim 1, wherein R² is1H-tetrazole, 2H-tetrazole, 1,2-oxazole, 1,3-thiazole, optionallyunsubstituted or substituted with a member independently selected fromthe group consisting of: —CH₃, and —NH₂.
 17. A chemical entity as inclaim 1, wherein R² is selected from the group consisting of1,2,3-triazole and 1,2,4-triazole, each unsubstituted or substitutedwith a member selected from the group consisting of: —CH₃, —CH₂F, —CHF₂,—CF₃, —OCH₃, —OCH₂CH₃, —CN, —C(R¹)OH, —CH₂OCH₃, N(R^(b))₂, —NO₂,—CO₂CH₃, —CONH₂, cyclopropyl and —CH₂NH₂.
 18. A chemical entity as inclaim 1, wherein R² is

and R^(h) is a member selected from the group consisting of: —H, —CH₃,—CF₃, —CH₂F, —CHF₂, —OCH₃, —OCH₂CH₃, —CH₂OH, —C(CH₃)₂OH, —CH₂OCH₃, —NO₂,—NH₂, —NHCH₃, —N(CH₃)₂, —CN, —CONH₂, —CO₂CH₃, and -cyclopropyl.
 19. Achemical entity as in claim 1, wherein R² is

and R^(j) is a member selected from the group consisting of: —H, —CH₃,—CF₃, —OCH₃, —CH₂(OH), —C(CH₃)₂OH, —CH₂OCH₃, —CO₂CH₃, and —NO₂.
 20. Achemical entity as in claim 1, wherein R² is

and R^(k) is a member selected from the group consisting of: —H, —CH₃,—CF₃, —CH₂F, —CHF₂, —OCH₃, —OCH₂CH₃, —CH₂OH, —C(CH₃)₂OH, —CH₂OCH₃, —NO₂,—NH₂, —NHCH₃, —N(CH₃)₂, —CN, —CONH₂, —CO₂CH₃, and -cyclopropyl.
 21. Achemical entity as in claim 1, wherein R³ is

where R^(m) is a member selected from the group consisting of: —Cl, —F,—CH₃, —CHF₂, —CN, —OCH₃, —CH₂OH, —OCH₂CH₃, —OCF₃, —OCHF₂, —SO₂CH₃,—OCH(CH₃)₂,


22. A chemical entity as in claim 1, wherein R³ is a member selectedfrom the group consisting of: 3-chlorophenyl, 3-cyanophenyl,3-fluorophenyl, 3-methylphenyl, 3-methoxyphenyl, 3-ethoxyphenyl,3-(trifluoromethoxy)phenyl, 3-(difluoromethoxy)phenyl and3-(difluoromethyl)phenyl.
 23. A chemical entity as in claim 1, whereinR³ is

substituted or unsubstituted with R^(n), where R^(n) is a memberselected from the group consisting of: —Cl, —CH₃, —OCH₃, —OCH₂CH₃,—OCHF₂, and —OCF₃.
 24. A chemical entity as in claim 1, wherein R³ is amember selected from the group consisting of: 4-chlorothiophen-2-yl,4-chloro-1H-pyrazol-1-yl, 1-methyl-1H-pyrazol-4-yl, and 1H-pyrazol-4-yl.25. A chemical entity as in claim 1, wherein R⁴ is a member selectedfrom the group consisting of —CH₃, —CH₂CH₃, —CH(CH₃)₂, and —CHF₂.
 26. Achemical entity, selected from the group consisting of:2-Chloro-5-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine;{2-[(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)amino]ethyl}dimethylamine;2-Methoxy-3-(6-methoxypyridin-2-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;2-Methoxy-3-(3-methylphenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;2-Methoxy-3-(5-methylpyridin-3-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;2-Methoxy-3-(2-methylpyridin-4-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;{3-[2-Methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridin-3-yl]phenyl}methanol;3-(3-Methanesulfonylphenyl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;2-Methoxy-3-(4-methylpyridin-2-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;2-Methoxy-3-(6-methylpyridin-2-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;2-(Difluoromethoxy)-3-(3-methylphenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methanol;1-[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]-1-(4-fluorophenyl)ethan-1-ol;[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl](5-fluoropyridin-2-yl)methanol;{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methyl}(methyl)amine;[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methanamine;{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methyl}dimethylamine;3-(3-Chlorophenyl)-5-[fluoro(4-fluorophenyl)methyl]-2-methoxypyridine;4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}benzoic acid;5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxylicacid;5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxamide;5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine;(4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)urea;4-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}benzamide;3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1H-pyrazol-4-ylmethyl)pyridine;5-{[6-(Difluoromethoxy)-5-(3-methoxyphenyl)pyridin-3-yl]methyl}pyrimidin-2-amine;5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridin-2-amine;1-(4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)-3-(oxetan-3-yl)urea;3-(3-Chlorophenyl)-2-methoxy-5-[(6-methoxypyridin-3-yl)methyl]pyridine;5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridin-2-amine;5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N,N-dimethylpyridin-2-amine;5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyrimidine-2-carbonitrile;5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1,3-thiazol-2-amine;(2-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)methanol;5-{[5-(3-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine;5-{[5-(3-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carbonitrile;5-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}pyrimidin-2-amine;5-{[5-(3-Chlorophenyl)-6-(propan-2-yloxy)pyridin-3-yl]methyl}pyrimidin-2-amine;5-{[6-(Difluoromethoxy)-5-[3-(propan-2-yloxy)phenyl]pyridin-3-yl]methyl}pyrimidin-2-amine;5-{[6-(Difluoromethoxy)-5-[3-(oxetan-3-yloxy)phenyl]pyridin-3-yl]methyl}pyrimidin-2-amine;N-(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)acetamide;3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(4-methanesulfonylphenyl)methyl]pyridine;5-{[6-(Difluoromethoxy)-5-(2-methoxypyridin-4-yl)pyridin-3-yl]methyl}pyrimidin-2-amine;5-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)pyrimidin-2-amine;2-[5-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)pyrimidin-2-yl]propan-2-ol;3-(3-Chlorophenyl)-2-methoxy-5-{[6-(trifluoromethyl)pyridin-3-yl]methyl}pyridine;3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-{[6-(propan-2-yloxy)pyridin-3-yl]methyl}pyridine;3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(6-propoxypyridin-3-yl)methyl]pyridine;5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1-methyl-1,2-dihydropyridin-2-one;3-(3-Chlorophenyl)-2-methoxy-5-(pyridin-4-ylmethyl)pyridine;5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridine-2-carboxylicacid;(4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)methanamine;4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridin-2-amine;3-(3-Chlorophenyl)-5-[(2,6-dimethylpyridin-4-yl)methyl]-2-methoxypyridine;4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridine-2-carbonitrile;4-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridine-2-carboxamide;3-(3-Chlorophenyl)-2-methoxy-5-(pyridin-3-ylmethyl)pyridine;3-(3-Chlorophenyl)-2-methoxy-5-(1,3-thiazol-5-ylmethyl)pyridine;3-(3-Chlorophenyl)-5-[(dimethyl-1,3-thiazol-5-yl)methyl]-2-methoxypyridine;3-(3-Chlorophenyl)-2-methoxy-5-[(6-methoxy-5-methylpyridin-3-yl)methyl]pyridine;3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1,3-thiazol-5-ylmethyl)pyridine;3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(dimethyl-1,3-thiazol-5-yl)methyl]pyridine;5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridine-3-carboxamide;(5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridin-3-yl)methanamine;3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(6-methylpyridin-3-yl)methyl]pyridine;3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(2-methyl-1,3-thiazol-5-yl)methyl]pyridine;3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1,3-thiazol-2-ylmethyl)pyridine;5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-2-methylpyrimidine;5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-2-methoxypyrimidine;5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N-(propan-2-yl)pyrimidin-2-amine;5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine;3-(3-Chlorophenyl)-2-methoxy-5-[(1-methyl-1H-pyrazol-4-yl)methyl]pyridine;3-(3-Chlorophenyl)-2-methoxy-5-(1H-pyrazol-4-ylmethyl)pyridine;5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N-methylpyrimidin-2-amine;5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N-cyclopropylpyrimidin-2-amine;5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N,N-dimethylpyrimidin-2-amine;5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N-(2,2,2-trifluoroethyl)pyrimidin-2-amine;3-(3-Chlorophenyl)-5-[(4-fluorophenyl)methyl]-2-methoxypyridine;5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyrimidin-2-amine;5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-N-cyclopropylpyrimidin-2-amine;5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-2-methoxypyrimidine;5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-N-methylpyrimidin-2-amine;5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-N-(2,2,2-trifluoroethyl)pyrimidin-2-amine;3-(3-Chlorophenyl)-2-methoxy-5-(1,2-oxazol-4-ylmethyl)pyridine;3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1,2-oxazol-4-ylmethyl)pyridine;3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(dimethyl-1,2-oxazol-4-yl)methyl]pyridine;Methyl2-(4-{[5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}phenyl)acetate;Ethyl1-(4-{[5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}phenyl)cyclopropane-1-carboxylate;3-(3-Chlorophenyl)-5-{[6-(cyclopropylmethoxy)pyridin-3-yl]methyl}-2-(difluoromethoxy)pyridine;3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(pyridin-2-ylmethyl)pyridine;2-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyrazine;6-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridazin-3-amine;3-(3-Chlorophenyl)-2-methoxy-6-methyl-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridine-2-carboxamide;5-{[6-(Difluoromethoxy)-5-(3-methoxyphenyl)pyridin-3-yl]methyl}pyrimidine-2-carboxamide;5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridine-2-carboxamide;5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyrimidine-2-carboxamide;5-{[5-(3-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxamide;5-({5-[3-(Difluoromethoxy)phenyl]-6-ethoxypyridin-3-yl}methyl)pyrimidine-2-carboxamide;5-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)pyrimidine-2-carboxamide;5-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)pyrimidine-2-carboxamide;5-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-ethoxypyridin-3-yl}methyl)pyrimidine-2-carboxamide;3-(3-Chlorophenyl)-5-[(3-cyclopropyl-1H-1,2,4-triazol-1-yl)methyl]-2-(difluoromethoxy)pyridine;3-(3-Fluorophenyl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;3-(3-Chlorophenyl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;3-(3-Chlorophenyl)-2-(propan-2-yloxy)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;3-[2-Methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridin-3-yl]benzonitrile;2-Methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)-3-[3-(trifluoromethoxy)phenyl]pyridine;3-(3-Chlorophenyl)-2-methoxy-5-[(3-methyl-4H-1,2,4-triazol-4-yl)methyl]pyridine;3-(3,5-Difluorophenyl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;Methyl1-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazole-5-carboxylate;Methyl1-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazole-3-carboxylate;3-(4-Chlorothiophen-2-yl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;3-(3-Chlorophenyl)-2-methoxy-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyridine;3-[3-(Difluoromethyl)phenyl]-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;3-(3-Chlorophenyl)-2-methoxy-5-(1H-pyrazol-1-ylmethyl)pyridine;3-(3-Chlorophenyl)-2-methoxy-5-{[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;3-(3-Chlorophenyl)-5-[(3-cyclopropyl-1H-1,2,4-triazol-1-yl)methyl]-2-methoxypyridine;3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyridine;3-(3-Chlorophenyl)-2-methoxy-5-{[4-(trifluoromethyl)-1H-imidazol-1-yl]methyl}pyridine;3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[1-(1H-1,2,4-triazol-1-yl)ethyl]pyridine;3-(3-Fluorophenyl)-2-methoxy-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyridine;3-(3-Chlorophenyl)-2-ethoxy-5-{[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;3-(3-Chlorophenyl)-2-ethoxy-5-{[5-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(4-methyl-1H-imidazol-1-yl)methyl]pyridine;3-[3-(Difluoromethoxy)phenyl]-2-methoxy-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyridine;1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-1,2,4-triazole-3-carbonitrile;3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-{[3-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-{[5-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;3-[3-(Difluoromethoxy)phenyl]-2-methoxy-5-{[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;3-[3-(Difluoromethoxy)phenyl]-2-methoxy-5-{[5-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1H-1,2,3,4-tetrazol-1-ylmethyl)pyridine;3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(2H-1,2,3,4-tetrazol-2-ylmethyl)pyridine;3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[5-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[3-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[5-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;5-[(4-Chloro-1H-pyrazol-1-yl)methyl]-3-[3-(difluoromethoxy)phenyl]-2-methoxypyridine;1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazole-3-carboxamide;Ethyl1-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-4-carboxylate;1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-4-carbonitrile;2-Methoxy-3-(pyridin-4-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;N-(1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazol-4-yl)acetamide;3-(3-Chlorophenyl)-5-(1H-imidazol-1-ylmethyl)-2-methoxypyridine;2-(Difluoromethoxy)-3-(3-fluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;2-(Difluoromethoxy)-3-(3-methoxyphenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;2-(Difluoromethoxy)-5-(1H-1,2,4-triazol-1-ylmethyl)-3-[3-(trifluoromethoxy)phenyl]pyridine;1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1,2-dihydropyridin-2-one;5-[(4-Chloro-1H-pyrazol-1-yl)methyl]-3-(3-chlorophenyl)-2-methoxypyridine;3-(3-Chlorophenyl)-2-methoxy-5-[(4-methyl-1H-pyrazol-1-yl)methyl]pyridine;3-(3-Chlorophenyl)-2-methoxy-5-[(4-nitro-1H-pyrazol-1-yl)methyl]pyridine;1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-imidazole-4-carboxamide;(1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol;[1-({5-[3-(Difluoromethoxy)phenyl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol;[1-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol;(1-((5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl)methyl)-1H-1,2,4-triazol-3-yl)methanol;(1-{[6-(Difluoromethoxy)-5-(3-ethoxyphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol;[1-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol;[1-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol;(1-{[6-(Difluoromethoxy)-5-[2-(difluoromethoxy)pyridin-4-yl]pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol;3-(3-Chlorophenyl)-2-methoxy-5-[(3-methoxy-1H-1,2,4-triazol-1-yl)methyl]pyridine;3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(3-methoxy-1H-1,2,4-triazol-1-yl)methyl]pyridine;3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(5-methoxy-1H-1,2,4-triazol-1-yl)methyl]pyridine;3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(3-ethoxy-1H-1,2,4-triazol-1-yl)methyl]pyridine;1-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-amine;1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine;1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine;1-{[5-(3-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine;1-{[6-Methoxy-5-(3-methoxyphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine;1-{[6-Methoxy-5-(3-methylphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine;3-{5-[(3-Amino-1H-1,2,4-triazol-1-yl)methyl]-2-methoxypyridin-3-yl}benzonitrile;1-{[5-(3-Ethoxyphenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine;1-{[5-(3-Cyclopropoxyphenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine;1-({5-[3-(Difluoromethoxy)phenyl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-amine;1-{[6-(Difluoromethoxy)-5-(3-methoxyphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine;1-{[5-(5-Chloropyridin-3-yl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine;1-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-amine;1-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-amine;1-{[6-(Difluoromethoxy)-5-[2-(difluoromethoxy)pyridin-4-yl]pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine;1-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-pyrazol-3-amine;1-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-pyrazol-5-amine;4-Chloro-1-{[5-(3-chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazol-3-amine;4-Chloro-1-{[5-(3-chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazol-5-amine;1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-N-methyl-1H-1,2,4-triazol-3-amine;1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-N,N-dimethyl-1H-1,2,4-triazol-3-amine;(1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanamine;1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazole-3-carboxamide;2-Methoxy-3-(1H-pyrazol-4-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N-(oxetan-3-yl)benzamide;5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-N-methylpyridine-2-carboxamide;1-(4-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}phenyl)cyclopropane-1-carboxamide;2-(4-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}phenyl)acetamide;2-(1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)propan-2-ol;2-Methoxy-3-(1-methyl-1H-pyrazol-4-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;2-(1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-5-yl)propan-2-ol;2-(4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)propan-2-ol;2-(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridin-2-yl)propan-2-ol;2-(5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridin-2-yl)propan-2-ol;3-[3-(Difluoromethoxy)phenyl]-5-{[3-(fluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}-2-methoxypyridine;3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[4-(fluoromethyl)-1H-1,2,3-triazol-1-yl]methyl}pyridine;2-(Difluoromethoxy)-3-(3-ethoxyphenyl)-5-{[3-(fluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;3-[2-(Difluoromethoxy)pyridin-4-yl]-5-{[3-(fluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}-2-methoxypyridine;3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-{[3-(difluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;3-[3-(Difluoromethoxy)phenyl]-5-{[3-(difluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}-2-ethoxypyridine;3-[2-(Difluoromethoxy)pyridin-4-yl]-5-{[3-(difluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}-2-methoxypyridine;3-(3-Chlorophenyl)-2-methoxy-5-(1H-1,2,3-triazol-1-ylmethyl)pyridine;[1-({5-[3-(Difluoromethoxy)phenyl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,3-triazol-4-yl]methanol;(1-((6-(Difluoromethoxy)-5-(3-ethoxyphenyl)pyridin-3-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol;3-[3-(Difluoromethoxy)phenyl]-5-{[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]methyl}-2-ethoxypyridine;1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-4-carboxylicacid;1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-4-carboxamide;[1-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-pyrazol-4-yl]methanol;(1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-imidazol-5-yl)methanol;(1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-imidazol-4-yl)methanol;[1-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-pyrazol-3-yl]methanol;(1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazol-4-yl)methanol;(4-Chloro-1-{[5-(3-chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazol-3-yl)methanol;(4-Chloro-1-{[5-(3-chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazol-5-yl)methanol;3-(4-Chloro-1H-pyrazol-1-yl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;4-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}benzoicacid; and pharmaceutically acceptable salts thereof.
 27. Apharmaceutical composition comprising an effective amount of at leastone chemical entity selected from the compounds of Formula (I):

wherein: Z is CH; R¹ is a member selected from the group consisting of:—H, —C₁₋₃alkyl and —C₁₋₃haloalkyl; Y is —C(R^(a))₂—, where each R^(a) isindependently selected from the group consisting of: —H, —F, —CH₃, —OHand —N(R^(b))₂; R² is a member selected from the group consisting of: A)phenyl unsubstituted or substituted with one or two R^(c) members, whereeach R^(c) is independently selected from the group consisting of: halo,—CN, —CO₂R^(b), —CONH₂, —SO₂CH₃, —C(R^(b))₂OH, —CH₂NH₂, —CH₂CONH₂,—CH₂CO₂CH₃, —NHCONH₂, —NHCONH-oxetane, —CONH-oxetane,

B) six-membered monocyclic heteroaromatic ring containing one or twonitrogen members unsubstituted or substituted with one or two memberseach independently selected from the group consisting of: halo, —C₁₋₃alkyl, —C₁₋₃haloalkyl, —CN, —C(R^(b))₂OH, —CH₂NH₂, —OC₁₋₃ alkyl,—O—CH₂-cyclopropyl, —CO₂H, —CON(R^(b))₂, —N(R^(b))₂, —NHCH₂CF₃,—NHCH(CH₃)₂, —NHCH₂CH₂N(CH₃)₂, —NHcyclopropyl, and —NHCOCH₃; C)five-membered monocyclic heteroaromatic ring containing two or threenitrogen members unsubstituted or substituted with one or two memberseach independently selected from the group consisting of halo, —C₁₋₃alkyl, —C₁₋₃haloalkyl, —C(R^(b))₂OH, —N(R^(b))₂, —NO₂, —CN, —OC₁₋₃alkyl, —CH₂OCH₃, —CH₂NH₂, —CO₂C₁₋₃alkyl, —CO₂H, —CONH₂, —NHCOCH₃, andcyclopropyl; and D) five or six-membered heteroaromatic ring selectedfrom: 1,2-dihydro-pyridin-2-one, tetrazole, thiazole or oxazoleunsubstituted or substituted with one or two members each independentlyselected from the group consisting of —H, —CH₃, and —NH₂; R³ is a memberselected from the group consisting of: phenyl, pyridyl, thiophene, andpyrazole, each unsubstituted or substituted with a member selected fromthe group consisting of: halo, —C₁₋₃ alkyl, —C₁₋₃ halo alkyl,—Ocyclopropyl, —OC₁₋₃haloalkyl, —CN, —CH₂OH and —SO₂CH₃; R⁴ is a memberselected from the group consisting of —C₁₋₃alkyl and —C₁₋₃haloalkyl;where each R^(b) is independently selected from —H or —CH₃; andpharmaceutically acceptable salt of compounds of Formula (I).
 28. Apharmaceutical composition comprising an effective amount of at leastone chemical entity of claim
 1. 29. A chemical entity as in claim 1,wherein the chemical entity is a compound of Formula (I).
 30. Acomposition of claim 1, wherein the chemical entity is selected fromcompounds of Formula (I) and pharmaceutically acceptable salts ofcompounds of Formula (I).